Hydrogels and Nanogels: Pioneering the Future of Advanced Drug Delivery Systems

Academic Editor: Helena Tomás Received: 26 December 2024 Revised: 22 January 2025 Accepted: 5 February 2025 Published: 7 February 2025 Citation: Delgado-Pujol, E.J.; Martínez, G.; Casado-Jurado, D.; Vázquez, J.; León-Barberena, J.; Rodríguez-Lucena, D.; Torres, Y.; Alcudia, A.; Begines, B. Hydrogels and Nanogels: Pioneering the Future of Advanced Drug Delivery Systems. Pharmaceutics 2025,17, 215. https://doi.org/10.3390/ pharmaceutics17020215 Correction Statement: This article has been republished with a minor change. Thechangedoesnotaffectthescientific contentofthearticleandfurther details are available within the backmatter of the website version of this article. Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/). Review Hydrogels and Nanogels: Pioneering the Future of Advanced Drug Delivery Systems Ernesto J. Delgado-Pujol 1,2,† , Guillermo Martínez 1,† , David Casado-Jurado 1,3, Juan Vázquez 4,* , Jesús León-Barberena 4, David Rodríguez-Lucena 1, Yadir Torres 2, Ana Alcudia 1and Belén Begines 1,* 1Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain; [email protected] (E.J.D.-P.); [email protected] (G.M.); [email protected] (D.C.-J.); [email protected] (D.R.-L.); [email protected] (A.A.) 2Departamento de Ingeniería y Ciencia de los Materiales y del Transporte, Escuela Politécnica Superior, Universidad de Sevilla, 41011 Sevilla, Spain; [email protected] 3 Departamento de Citología e Histología Normal y Patológica, Facultad de Medicina, Universidad de Sevilla, 41009 Sevilla, Spain 4Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, 41012 Sevilla, Spain; [email protected] *Correspondence: [email protected] (J.V.); [email protected] (B.B.) †These authors contributed equally to this work. Abstract: Conventional drug delivery approaches, including tablets and capsules, often suffer from reduced therapeutic effectiveness, largely attributed to inadequate bioavailability and difficulties in ensuring patient adherence. These challenges have driven the development of advanced drug delivery systems (DDS), with hydrogels and especially nanogels emerging as promising materials to overcome these limitations. Hydrogels, with their biocompatibility, high water content, and stimuli-responsive properties, provide controlled and targeted drug release. This review explores the evolution, properties, and classifications of hydrogels versus nanogels and their applications in drug delivery, detailing synthesis methods, including chemical crosslinking, physical self-assembly, and advanced techniques such as microfluidics and 3D printing. It also examines drug-loading mechanisms (e.g., physical encapsulation and electrostatic interactions) and release strategies (e.g., diffusion, stimuli-responsive, and enzyme-triggered). These gels demonstrate significant advantages in addressing the limitations of traditional DDS, offering improved drug stability, sustained release, and high specificity. Their adaptability extends to various routes of administration, including topical, oral, and injectable forms, while emerging nanogels further enhance therapeutic targeting through nanoscale precision and stimuli responsiveness. Although hydrogels and nanogels have transformative potential in personalized medicine, challenges remain in scalable manufacturing, regulatory approval, and targeted delivery. Future strategies include integrating biosensors for real-time monitoring, developing dual-stimuli-responsive systems, and optimizing surface functionalization for specificity. These advancements aim to establish hydrogels and nanogels as cornerstones of next-generation therapeutic solutions, revolutionizing drug delivery, and paving the way for innovative, patient-centered treatments. Keywords: hydrogels for drug delivery; nanogels in therapeutics; stimuli-responsive drug delivery systems; personalized medicine with hydrogels; biocompatible polymer networks 1. Introduction Traditional drug delivery methods, including tablets, capsules, and syrups, have long been the cornerstone of pharmacological treatments. However, these conventional Pharmaceutics 2025,17, 215 https://doi.org/10.3390/pharmaceutics17020215 Pharmaceutics 2025,17, 215 2 of 47 approaches present significant limitations in therapeutic efficacy, including challenges with drug stability and patient compliance. A primary limitation of these methods is their low bioavailability, defined as the proportion of the drug that successfully reaches the systemic circulation to exert its therapeutic effect. This inefficiency can be attributed to physiological barriers, such as degradation within the gastrointestinal tract and hepatic first-pass metabolism, which considerably reduce the effective drug reaching the target site [ 1 ]. Additionally, conventional delivery often results in rapid drug release, causing an initial spike in plasma concentration followed by a rapid decline. This fluctuation requires frequent dosing to maintain therapeutic levels, which can increase the risk of side effects and reduce patient adherence [2]. To address these challenges, the field of drug delivery has shifted towards advanced drug delivery systems (DDS), which offer innovative strategies to enhance therapeutic efficacy by controlling the dosage, timing, and site of drug release [ 3 ]. Among various DDS technologies, hydrogels have emerged as one of the most promising materials due to their unique physical and chemical properties, enabling the controlled release of therapeutic agents and targeted delivery to specific tissues. Hydrogels are highly hydrated threedimensional polymer networks that are capable of encapsulating and releasing drugs over a sustained period, making them suitable for treatments that require prolonged or targeted release [ 4 , 5 ]. Hydrogels were introduced in the early 1960s and pioneered by Wichterle and D. Lim [ 6 ], who developed the first hydrogel, poly (2-hydroxyethyl methacrylate) for use in contact lenses. This discovery marked the beginning of modern hydrogel technology, inspiring decades of research into hydrogels for biomedical applications beyond ocular use [ 7 ]. Since then, hydrogels have evolved significantly, with research expanding their applications to controlled drug delivery, where they have become essential due to their biocompatibility, high water content, and ability to mimic natural tissues [ 8 ]. These characteristics allow hydrogels to encapsulate drugs while protecting them from enzymatic degradation, particularly important for sensitive biomolecules like peptides and proteins. Modern hydrogel systems are often described as “smart” materials due to their ability to respond to physiological stimuli such as pH, temperature, or biochemical signals, enabling precise, on-demand drug release [ 9 ]. This responsiveness allows smart hydrogels to release therapeutic agents selectively in target environments, such as acidic tumor tissues or inflamed regions, where specific conditions trigger drug release. This adaptability is crucial for applications requiring high specificity, like cancer treatment, where minimizing systemic toxicity is paramount [10]. In terms of structure, hydrogels are formed by crosslinked polymer chains, arranged in a three-dimensional network that stabilizes the material. This crosslinked structure enables the hydrogel to retain a practically ‘infinite’ molecular weight, a concept that, while not literal, highlights the unique network properties not observed in simpler polymers [ 11 ]. Figure 1illustrates the general structure of a hydrogel, highlighting key features such as the crosslinked polymer network and possible bonding types, including both covalent and reversible interactions that contribute to the stability and responsiveness of the hydrogel [ 12 ]. The 3D configuration of the material is produced by the crosslinking of different polymer chains that appear, in turn, through the generation of chemical bonds (permanent connections that provide stability of the network) or physical bonds (interactions such as hydrogen bonds or hydrophobic interactions that can break and reform, allowing some flexibility and response to stimulus in the hydrogel). The appearance of entanglement is also common due to the physical interconnection of polymer chains with each other without forming chemical bonds [ 12 ]. Although covalent bonds provide a more stable and robust structure, physical bonds, although weaker, allow for the reversibility Pharmaceutics 2025,17, 215 3 of 47 and flexibility of the hydrogel. This duality in crosslinking methods broadens the range of possible applications for hydrogels [13]. Pharmaceutics 2025, 17, x FOR PEER REVIEW 3 of 50 stable and robust structure, physical bonds, although weaker, allow for the reversibility and flexibility of the hydrogel. This duality in crosslinking methods broadens the range of possible applications for hydrogels [13]. Figure 1. General structure of a hydrogel, including the potential polymer interactions required to create and reinforce the 3D structure. The versatility of hydrogels allows them to be administered through various routes, each offering unique advantages depending on therapeutic requirements and target tissue: 1. Topical Application: Hydrogels are ideal for topical use because of their high water content, which provides a moist environment beneficial for wound healing and tissue repair. They are widely applied in skin treatments, burns, and ulcers. Nanogels, with their enhanced penetration abilities, can deliver drugs deeper into the skin, making them effective for localized cancer therapies and the treatment of chronic skin diseases [14]. 2. Oral Administration: Oral hydrogels are designed to swell upon contact with gastrointestinal fluids, gradually releasing drugs as they move through the GI tract. Bioadhesive hydrogels adhere to the mucosal surface, enhancing bioavailability for drugs with poor absorption rates. This sustained release can be beneficial for drugs that require prolonged delivery or protection against gastric degradation [15]. 3. Buccal Administration: Due to their bioadhesive properties, hydrogels are suitable for oral drug delivery, allowing sustained release through the buccal mucosa and bypassing first-pass metabolism, which is advantageous for drugs susceptible to liver degradation [16]. 4. Injectable Administration: Injectable hydrogels offer a minimally invasive option for sustained drug release directly into the systemic circulation or targeted tissues. After injection, these hydrogels form stable depots that gradually release the drug, improving therapeutic outcomes by focusing the treatment locally. Injectable nanogels add additional targeting capabilities, minimizing systemic side effects [17]. 5. Other Routes: Hydrogels are also utilized in transdermal patches, ophthalmic solutions, and intranasal delivery systems. For instance, intranasal nanogels bypass the blood–brain barrier, enabling direct delivery of therapeutics to the central nervous system [18]. Figure 1. General structure of a hydrogel, including the potential polymer interactions required to create and reinforce the 3D structure. The versatility of hydrogels allows them to be administered through various routes, each offering unique advantages depending on therapeutic requirements and target tissue: 1. Topical Application: Hydrogels are ideal for topical use because of their high water content, which provides a moist environment beneficial for wound healing and tissue repair. They are widely applied in skin treatments, burns, and ulcers. Nanogels, with their enhanced penetration abilities, can deliver drugs deeper into the skin, making them effective for localized cancer therapies and the treatment of chronic skin diseases [14]. 2. Oral Administration: Oral hydrogels are designed to swell upon contact with gastrointestinal fluids, gradually releasing drugs as they move through the GI tract. Bioadhesive hydrogels adhere to the mucosal surface, enhancing bioavailability for drugs with poor absorption rates. This sustained release can be beneficial for drugs that require prolonged delivery or protection against gastric degradation [15]. 3. Buccal Administration: Due to their bioadhesive properties, hydrogels are suitable for oral drug delivery, allowing sustained release through the buccal mucosa and bypassing first-pass metabolism, which is advantageous for drugs susceptible to liver degradation [16]. 4. Injectable Administration: Injectable hydrogels offer a minimally invasive option for sustained drug release directly into the systemic circulation or targeted tissues. After injection, these hydrogels form stable depots that gradually release the drug, improving therapeutic outcomes by focusing the treatment locally. Injectable nanogels add additional targeting capabilities, minimizing systemic side effects [17]. 5. Other Routes: Hydrogels are also utilized in transdermal patches, ophthalmic solutions, and intranasal delivery systems. For instance, intranasal nanogels bypass the blood–brain barrier, enabling direct delivery of therapeutics to the central nervous system [18]. Despite their promise, hydrogels face several technical challenges that limit their widespread clinical use. Issues such as precise control over gelation, potential immuno- Pharmaceutics 2025,17, 215 4 of 47 genicity, and challenges in scaling up production for clinical applications remain areas of active research [ 19 ]. Researchers continue to explore ways to improve the performance of hydrogels, focusing on new crosslinking strategies, enhanced stability, and the development of hydrogels that can degrade safely in the body after treatment [ 20 ]. The integration of nanocarriers, such as nanoparticles or liposomes, into hydrogel matrices also represents a promising strategy to enhance drug loading capacity and release profiles, broadening the therapeutic potential of these systems [21]. In this review, different aspects of hydrogels are explored, including their physicochemical properties, their classifications, and the various types of hydrogels and nanogels used in drug delivery applications (Figure 2). The challenges and recent innovations in hydrogel technology are also discussed, emphasizing the role of hydrogels in advancing personalized medicine and sustainable therapeutic solutions. Through these explorations, the aim was to highlight the transformative potential of hydrogel-based DDS to overcome the limitations of conventional drug delivery methods and to pave the way for new, patient-centered therapeutic strategies. Pharmaceutics 2025, 17, x FOR PEER REVIEW 4 of 50 Despite their promise, hydrogels face several technical challenges that limit their widespread clinical use. Issues such as precise control over gelation, potential immunogenicity, and challenges in scaling up production for clinical applications remain areas of active research [19]. Researchers continue to explore ways to improve the performance of hydrogels, focusing on new crosslinking strategies, enhanced stability, and the development of hydrogels that can degrade safely in the body after treatment [20]. The integration of nanocarriers, such as nanoparticles or liposomes, into hydrogel matrices also represents a promising strategy to enhance drug loading capacity and release profiles, broadening the therapeutic potential of these systems [21]. In this review, different aspects of hydrogels are explored, including their physicochemical properties, their classifications, and the various types of hydrogels and nanogels used in drug delivery applications (Figure 2). The challenges and recent innovations in hydrogel technology are also discussed, emphasizing the role of hydrogels in advancing personalized medicine and sustainable therapeutic solutions. Through these explorations, the aim was to highlight the transformative potential of hydrogel-based DDS to overcome the limitations of conventional drug delivery methods and to pave the way for new, patient-centered therapeutic strategies. Figure 2. Schematics of the different sections addressed in this literature review. 2. Classification of Hydrogels Hydrogels can be classified on the basis of various criteria, including their source, composition, crosslinking methods, and responsiveness to environmental stimuli. This classification not only provides a framework for understanding the structural and functional diversity of hydrogels but also serves as a guide for selecting appropriate hydrogels for specific drug delivery applications (see Figure 3 for a schematic overview of the hydrogel classification). Figure 3. Classification of hydrogels. Figure 2. Schematics of the different sections addressed in this literature review. 2. Classification of Hydrogels Hydrogels can be classified on the basis of various criteria, including their source, composition, crosslinking methods, and responsiveness to environmental stimuli. This classification not only provides a framework for understanding the structural and functional diversity of hydrogels but also serves as a guide for selecting appropriate hydrogels for specific drug delivery applications (see Figure 3for a schematic overview of the hydrogel classification). Pharmaceutics 2025, 17, x FOR PEER REVIEW 4 of 50 Despite their promise, hydrogels face several technical challenges that limit their widespread clinical use. Issues such as precise control over gelation, potential immunogenicity, and challenges in scaling up production for clinical applications remain areas of active research [19]. Researchers continue to explore ways to improve the performance of hydrogels, focusing on new crosslinking strategies, enhanced stability, and the development of hydrogels that can degrade safely in the body after treatment [20]. The integration of nanocarriers, such as nanoparticles or liposomes, into hydrogel matrices also represents a promising strategy to enhance drug loading capacity and release profiles, broadening the therapeutic potential of these systems [21]. In this review, different aspects of hydrogels are explored, including their physicochemical properties, their classifications, and the various types of hydrogels and nanogels used in drug delivery applications (Figure 2). The challenges and recent innovations in hydrogel technology are also discussed, emphasizing the role of hydrogels in advancing personalized medicine and sustainable therapeutic solutions. Through these explorations, the aim was to highlight the transformative potential of hydrogel-based DDS to overcome the limitations of conventional drug delivery methods and to pave the way for new, patient-centered therapeutic strategies. Figure 2. Schematics of the different sections addressed in this literature review. 2. Classification of Hydrogels Hydrogels can be classified on the basis of various criteria, including their source, composition, crosslinking methods, and responsiveness to environmental stimuli. This classification not only provides a framework for understanding the structural and functional diversity of hydrogels but also serves as a guide for selecting appropriate hydrogels for specific drug delivery applications (see Figure 3 for a schematic overview of the hydrogel classification). Figure 3. Classification of hydrogels. Figure 3. Classification of hydrogels. Pharmaceutics 2025,17, 215 5 of 47 Source: Hydrogels are derived from natural or synthetic polymers. Natural hydrogels, such as those based on chitosan, collagen, or hyaluronic acid, are known for their biocompatibility, biodegradability, and intrinsic bioactivity, making them ideal for applications requiring high biological integration. However, they may lack mechanical strength and sometimes require reinforcement [ 22 ]. Synthetic hydrogels, made from polymers like poly(ethylene glycol) (PEG) and poly(vinyl alcohol) (PVA), offer greater control over mechanical and physicochemical properties, although they may require surface modifications to improve biocompatibility and reduce immunogenicity [ 12 ]. Semi-synthetic hydrogels combine natural and synthetic polymers to optimize both biological activity and mechanical properties, such as acrylate-modified hyaluronic acid [23]. Composition: Hydrogels can be composed of a single type of monomer (homopolymers) or multiple types (copolymers), where at least one hydrophilic monomer facilitates water absorption (Figure 4). Interpenetrating polymer networks (IPNs) and semi-IPNs are advanced forms of hydrogel structures. IPNs consist of two crosslinked polymers interwoven within each other, while semi-IPNs integrate a crosslinked polymer network with a noncrosslinked counterpart, providing a combination of stability and flexibility ideal for drug delivery applications where adaptability and structural integrity are essential [24]. Pharmaceutics 2025, 17, x FOR PEER REVIEW 5 of 50 Source: Hydrogels are derived from natural or synthetic polymers. Natural hydrogels, such as those based on chitosan, collagen, or hyaluronic acid, are known for their biocompatibility, biodegradability, and intrinsic bioactivity, making them ideal for applications requiring high biological integration. However, they may lack mechanical strength and sometimes require reinforcement [22]. Synthetic hydrogels, made from polymers like poly(ethylene glycol) (PEG) and poly(vinyl alcohol) (PVA), offer greater control over mechanical and physicochemical properties, although they may require surface modifications to improve biocompatibility and reduce immunogenicity [12]. Semi-synthetic hydrogels combine natural and synthetic polymers to optimize both biological activity and mechanical properties, such as acrylate-modified hyaluronic acid [23]. Composition: Hydrogels can be composed of a single type of monomer (homopolymers) or multiple types (copolymers), where at least one hydrophilic monomer facilitates water absorption (Figure 4). Interpenetrating polymer networks (IPNs) and semi-IPNs are advanced forms of hydrogel structures. IPNs consist of two crosslinked polymers interwoven within each other, while semi-IPNs integrate a crosslinked polymer network with a non-crosslinked counterpart, providing a combination of stability and flexibility ideal for drug delivery applications where adaptability and structural integrity are essential [24]. Figure 4. Classification of hydrogels according to their composition. Crystallinity: According to the crystallization state of the polymer, hydrogels can be found as amorphous (an irregular random polymeric network with no crystalline order); crystalline (a highly compact and ordered polymer network) or semicrystalline (contains both amorphous and crystalline regions, with rapid phase transitions useful for injectable hydrogels and shape memory applications) [12,23]. Figure 4. Classification of hydrogels according to their composition. Crystallinity: According to the crystallization state of the polymer, hydrogels can be found as amorphous (an irregular random polymeric network with no crystalline order); crystalline (a highly compact and ordered polymer network) or semicrystalline (contains both amorphous and crystalline regions, with rapid phase transitions useful for injectable hydrogels and shape memory applications) [12,23]. Pharmaceutics 2025,17, 215 6 of 47 Crosslinking Method: Crosslinking, a critical aspect of the hydrogel structure, affects the stability and swelling behavior. Chemically crosslinked hydrogels, formed through covalent bonds, provide stable structures that are less susceptible to environmental changes, which can be beneficial for long-term drug release applications. In contrast, physically crosslinked hydrogels, which rely on ionic or hydrogen bonds, offer greater flexibility and responsiveness, allowing the hydrogel to adapt to stimuli in the physiological environment [25]. Ionic charge: Hydrogels can be non-ionic (neutral), ionic (anionic or cationic), amphoteric (containing acidic and basic groups), or zwitterionic (containing both anionic and cationic groups in each repeating unit) [26]. Degradability: Hydrogels can be either durable (e.g., polyacrylate-based) or biodegradable (e.g., polysaccharide-based) [27]. Stimuli Responsiveness: Conventional hydrogels undergo slight modifications in their structure, mainly through swelling, in response to external environmental conditions, and have low mechanical strength [ 23 ]. However, smart hydrogels are sensitive to small changes in environmental conditions and rapidly adjust their physical properties, such as mechanical strength, swelling capacity, permeability, and stimulus sensitivity [ 12 ]. In this sense, smart hydrogels can respond to physical stimuli (such as temperature, pressure, light, or electric and magnetic fields), chemical stimuli (such as pH, ionic strength, solvent composition, or molecular species), or biochemical stimuli (such as antigen, ligand, or enzyme response), affecting properties such as swelling and deformation [ 23 ] (Figure 5). For example, pH-sensitive hydrogels are designed to swell in acidic or basic environments, making them suitable for targeting specific regions of the gastrointestinal tract or tumor tissues, where pH variations can be exploited for localized drug release [ 28 ]. Similarly, temperature-sensitive hydrogels respond to changes in temperature, expanding or contracting to control drug release as needed [9]. Pharmaceutics 2025, 17, x FOR PEER REVIEW 6 of 50 Crosslinking Method: Crosslinking, a critical aspect of the hydrogel structure, affects the stability and swelling behavior. Chemically crosslinked hydrogels, formed through covalent bonds, provide stable structures that are less susceptible to environmental changes, which can be beneficial for long-term drug release applications. In contrast, physically crosslinked hydrogels, which rely on ionic or hydrogen bonds, offer greater flexibility and responsiveness, allowing the hydrogel to adapt to stimuli in the physiological environment [25]. Ionic charge: Hydrogels can be non-ionic (neutral), ionic (anionic or cationic), amphoteric (containing acidic and basic groups), or zwitterionic (containing both anionic and cationic groups in each repeating unit) [26]. Degradability: Hydrogels can be either durable (e.g., polyacrylate-based) or biodegradable (e.g., polysaccharide-based) [27]. Stimuli Responsiveness: Conventional hydrogels undergo slight modifications in their structure, mainly through swelling, in response to external environmental conditions, and have low mechanical strength [23]. However, smart hydrogels are sensitive to small changes in environmental conditions and rapidly adjust their physical properties, such as mechanical strength, swelling capacity, permeability, and stimulus sensitivity [12]. In this sense, smart hydrogels can respond to physical stimuli (such as temperature, pressure, light, or electric and magnetic fields), chemical stimuli (such as pH, ionic strength, solvent composition, or molecular species), or biochemical stimuli (such as antigen, ligand, or enzyme response), affecting properties such as swelling and deformation [23] (Figure 5). For example, pH-sensitive hydrogels are designed to swell in acidic or basic environments, making them suitable for targeting specific regions of the gastrointestinal tract or tumor tissues, where pH variations can be exploited for localized drug release [28]. Similarly, temperature-sensitive hydrogels respond to changes in temperature, expanding or contracting to control drug release as needed [9]. Figure 5. Main stimuli to which a hydrogel can be designed to respond. These classification criteria allow for the tailored design of hydrogels to meet specific drug delivery requirements, from sustained release in chronic conditions to responsive, localized release in targeted therapies. Figure 5. Main stimuli to which a hydrogel can be designed to respond. These classification criteria allow for the tailored design of hydrogels to meet specific drug delivery requirements, from sustained release in chronic conditions to responsive, localized release in targeted therapies. Pharmaceutics 2025,17, 215 7 of 47 3. Physical and Chemical Properties of Hydrogels The unique structural characteristics of hydrogels are determined by the polymer composition. The type of polymer used determines key parameters such as the biocompatibility, degradability, and drug loading capacity of the hydrogel [ 29 ]. In addition, the polymer composition can also affect surface functionality, allowing the introduction of functional groups on the surface of the hydrogel, enhancing their drug-loading capacity and controlled release. Functional groups such as carboxyl, amino, and hydroxyl enable the conjugation of drugs and other therapeutic agents, improving drug stability within the hydrogel [ 29 ]. For biomedical applications, biocompatibility is critical to allow hydrogels to interact with biomolecules such as drugs and cells [ 30 ]. Similarly, degradability is also an important factor because hydrogels can gradually degrade within the body, releasing drugs in a controlled manner without causing toxic effects. Degradation can be tailored by modifying the polymer composition and crosslinking density [ 31 ]. Crosslinking can be achieved chemically, forming permanent covalent bonds, or physically, creating reversible interactions like hydrogen bonds or ionic interactions. These crosslinked structures endow hydrogels with a degree of flexibility, stability, and responsiveness to various stimuli, such as pH, temperature, or mechanical stress, which can be exploited to control the release of encapsulated drugs [13]. Swelling capacity, one of the most crucial properties for drug release, begins with the absorption of water by the hydrophilic groups in the polymer chains. This absorption process allows the hydrogel network to expand, creating channels that facilitate drug diffusion. The degree of swelling is directly influenced by factors such as polymer concentration and crosslinking density; for example, a higher crosslinking density results in a more compact structure with reduced swelling capacity but enhanced mechanical stability, making it more suitable for applications that require longer-lasting release profiles [ 32 ]. Porosity influences the transport of nutrients, waste, and molecules through the hydrogel. Greater porosity facilitates the diffusion of larger molecules, while smaller pores allow for controlled drug release [ 33 ]. Elasticity and viscoelasticity are additional critical properties in hydrogels, especially in tissue engineering applications where the material must conform to irregular shapes and withstand physiological stresses. The dual behavior of viscoelasticity enables hydrogels to act as both stable and adaptable carriers, ensuring that they remain intact under physiological conditions while allowing gradual drug release [ 34 ]. Transparency is crucial in optical applications like contact lenses, allowing light to pass without significant scattering, and maintaining visual clarity [35]. The ability to fine tune these physicochemical properties is particularly valuable in the design of DDSs tailored to specific therapeutic needs, where drug release can be triggered by external or internal cues. 4. General Preparation Methods of Hydrogels Hydrogels are synthesized using various methods, each offering unique advantages in terms of structure, size, and functionality. The choice of preparation method significantly impacts the physicochemical properties of hydrogels, such as size uniformity, mechanical stability, and responsiveness to stimuli. Chemical Crosslinking: Chemical crosslinking involves the formation of covalent bonds within polymeric networks, yielding highly stable hydrogels. This method is commonly used to produce hydrogels with precise size and robust mechanical properties [ 36 ]. The uniformity of the properties usually leads to good control in drug delivery. Common examples of chemical crosslinking are photo-crosslinking, the use of crosslinking agents, or the application of Click chemistry reactions. In photo-crosslinking, UV or visible light is used to initiate crosslinking reactions in certain polymer systems. For example, PEG Pharmaceutics 2025,17, 215 8 of 47 and poly(vinyl alcohol) hydrogels can be crosslinked using UV light in the presence of a photoinitiator to create stable networks. This approach enables spatial and temporal control of hydrogel formation, making it particularly useful for creating patterned hydrogels and bioinks for 3D bioprinting [ 37 ]. Despite its advantages, photo-crosslinking can be limited by the potential cytotoxicity of photoinitiators and the depth of light penetration. Glutaraldehyde is a commonly used agent to crosslink polysaccharides like alginate or chitosan, creating strong, stable hydrogels for biomedical applications such as wound healing. Another example is epoxy-based crosslinkers, which are often used to form hydrogels for controlled drug delivery. This method ensures long-term structural integrity but requires the use of chemical agents, which can introduce cytotoxicity [ 38 ]. Click chemistry is a popular technique in hydrogel chemistry. It involves reactions like the azide-alkyne reaction to form highly efficient and specific covalent bonds [ 39 ]. This method is often used for creating functionalized hydrogels that can deliver drugs in a controlled manner. Mauri et al. [ 40 ] discussed the use of controlled polymerization techniques for precise chemical crosslinking to ensure reproducibility in hydrogel synthesis. It is worth mentioning chemical crosslinking using high-energy radiation, such as gamma rays or electron beams. It can be used to initiate polymerization and crosslinking in hydrogel synthesis. This method is particularly effective for producing sterile and biocompatible hydrogels. It avoids the need for chemical initiators, which makes it suitable for biomedical applications; however, it requires accessibility to high-energy radiation facilities. Physical Self-Assembly: Physical self-assembly relies on non-covalent interactions such as hydrogen bonding, hydrophobic interactions, or electrostatic forces to form hydrogels. This method is particularly suitable for sensitive drugs or biomolecules like proteins and nucleic acids, as it avoids harsh chemical conditions and preserves their bioactivity [ 41 , 42 ]. Ravarino et al. [ 43 ] described the self-assembly of a fluorine-containing dipeptide to form hydrogels via π - π stacking, hydrogen bonding, and halogen bonds. The hydrogel demonstrated excellent physical properties, making it useful for drug delivery and biomedical applications. Polymerization: Polymerization techniques can also be divided into emulsion polymerization and photopolymerization. Emulsion polymerization is a widely used technique in which monomers are polymerized within a dispersed phase (usually water) to form hydrogels. The method can produce hydrogels with a controlled size and high drug-loading efficiency, leading to scalable production, high size uniformity, and cost-effectiveness. However, it requires surfactants, which may need to be removed post-synthesis. Romero et al. [ 44 ] detailed the preparation of hydrogels using emulsion polymerization of N-vinyl caprolactam crosslinked with PEG diacrylate. The resulting hydrogels were thermoresponsive, exhibiting phase transitions near physiological temperature, making them suitable for controlled DDS. The drug release behavior was evaluated using colchicine as a model drug, demonstrating sustained and controlled release profiles. Photopolymerization involves initiating polymerization using light. It allows precise spatial and temporal control over nanogel formation. Typically, UV or visible light is used to activate a photoinitiator, leading to crosslinking of the polymer matrix. It allows high control over the polymerization process, minimal side reactions, and environmental responsiveness; however, it requires specialized equipment and may limit scalability. Y. Wang et al. [ 45 ] described the preparation of a semi-interpenetrating polymer networks hydrogel composed of PEG diacrylate and hyaluronic acid. The hydrogel, prepared via in situ UV photopolymerization, incorporated paclitaxel-loaded poly(lactic-coglycolic acid) nanoparticles. The system demonstrated effective local drug delivery, sustained release for up to 13 days, and significant tumor inhibition without toxic effects in vivo. Each synthesis process offers unique advantages and challenges. Chemical crosslinking is widely used due to its ability to produce hydrogels with robust mechanical properties Pharmaceutics 2025,17, 215 9 of 47 and tailored functionalities. However, the use of chemical crosslinkers or initiators often introduces cytotoxicity and necessitates extensive purification to ensure biocompatibility, limiting its direct applicability for biomedical purposes [ 46 ]. In contrast, physical selfassembly relies on non-covalent interactions such as hydrogen bonding, ionic interactions, and hydrophobic effects to form hydrogels, making it a safer and more environmentally friendly approach. While this method avoids the need for potentially harmful reagents, the resulting hydrogels often exhibit weaker mechanical properties and sensitivity to environmental conditions, which can limit their stability in physiological applications [ 47 ]. Polymerization techniques, including free-radical and controlled polymerization, allow for precise control over hydrogel composition and structure, enabling the incorporation of stimuli-responsive properties. However, these methods often require stringent reaction conditions and may involve toxic reagents, posing challenges for clinical translation [ 48 ]. Moving forward, hybrid approaches combining the strengths of these techniques while addressing their limitations—such as green chemistry-based crosslinking or advanced self-assembly methods enhanced by polymerization—may offer more versatile and scalable solutions for hydrogel fabrication. 5. Drug Loading and Release Mechanisms Hydrogels provide multiple mechanisms for drug loading, including physical encapsulation, covalent attachment, and electrostatic interactions [ 49 ]. This versatility allows for the inclusion of a wide range of therapeutic molecules, from small-molecule drugs to larger biomolecules like proteins and nucleic acids. Physical encapsulation is commonly used for hydrophilic or even hydrophobic drugs [ 50 ]. It is based on the physical entrapment of drugs inside hydrophilic vehicles. This method relies on the swelling and contraction properties of the hydrogels to retain the drug inside. Abdel-Rashid et al. [ 51 ] prepared a chitosanbased nanogel containing sorbitan monostearate–sodium deoxycholate nanovesicles loaded with acetazolamide for the delivery of ocular drugs. Electrostatic interactions are ideal for loading negatively or positively charged biomolecules, such as siRNA or DNA, which are often used in gene therapy applications [ 52 ]. Tang et al. [ 53 ] described the use of a DNA hydrogel linked by electrostatic interactions to antisense oligonucleotides. The hydrogel also carried chemotherapeutics, such as doxorubicin, for combined chemo/gene therapy of multidrug-resistant tumors. Covalent attachment is used when ionic species are required; for example, in theragnostic applications. Carniato et al. [ 54 ] prepared chitosan-based hydrogels using Mn(II) chelates as both covalent crosslinkers and contrast agents. Drug release from hydrogels can occur through various pathways, depending on the design and intended application. The most common release mechanisms include the following. 5.1. Diffusion-Controlled Release in Conventional Hydrogels Conventional hydrogels are defined by their stable, static network structure, which allows them to release drugs primarily through a diffusion-controlled mechanism. These hydrogels are particularly valuable for applications requiring sustained or prolonged drug release, as the gradual migration of drug molecules out of the hydrogel matrix provides a consistent dose over time. This characteristic makes conventional hydrogels highly suitable for managing chronic conditions, where maintaining a stable concentration of the drug in the bloodstream is essential to achieve therapeutic efficacy without frequent re-dosing [ 55 ]. A significant application of conventional hydrogels is in topical drug formulations, particularly in wound care and skin conditions. Their high water content provides a moist environment that promotes wound healing and tissue regeneration. This moist environment promotes autolytic debridement, a process that removes dead tissue without external intervention. It not only facilitates the migration of regenerative cells to the wound site, but Pharmaceutics 2025,17, 215 16 of 47 Table 2. Summary of pH-, temperatureand photo-sensitive hydrogels, including materials used for their synthesis and their application. Scheme Materials Applications Ref. pH-Responsive Carboxylated agarose, zinc ions, tannic acid Healing capabilities Tissue regeneration [89] Hydroxypropyl chitin, ferric ions, tannic acid [90] Alginate, carboxymethyl cellulose [91] Aldehyde-functionalized polymer, amine-modified silica nanoparticles Cancer therapy [96] N-carboxyethyl chitosan, PEG aldehyde [97] Dextran phosphate-based hydrogel, prospidine [98] Peptide hydrogel, paclitaxel [99] OE polypeptides [100] Methoxy PEG, cinnamaldehyde, adipic acid dihydrazide [101] PEG, polyacrylic acid, ezetimibe Hypercholesterolemia control [102] Polycaprolactone, methacrylic acid copolymer Radioprotective drug delivery [103] N-Succinyl hydroxybutyl chitosan Oral drug administration [104] Chitosan nanospheres Type 2 Diabetes management [105] TemperatureResponsive PEG-poly(ε-caprolactone)-PEG Hydrophobic drugs delivery [106] Poly(ε-caprolactone-co-lactide)-β-PEG-β-poly(εcaprolactone-co-lactide) Protein drug delivery [107] Methylcellulose, alginate [108] Poly(ether urethane) with pH-sensitive mesoporous silica nanoparticles Localized therapies [109] PEG, N-(2-hydroxypropyl) methacrylamide-mono dilactate, thiolated hyaluronic acid Neurological disorders treatment [110] Chitosan-based hydrogel, triptolide-loaded nanostructures Breast cancer therapy [111] Chitosan, agarose [112] Chitosan, β-glycerin sodium phosphate, glycyrrhetinic acid-modified graphene oxide Hepatocellular carcinoma therapy [113] Poloxamer, 5-fluorouracil Colorectal cancer [114] Photo-Responsive Chitosan, silk sericin Tegafur, Protoporphyrin IX Chemotherapy and Photodynamic therapy [115] Ti3C2Tx-based MXene [116] Agarose, manganese oxide nanoparticles, Chlorin E6 [117] Silk fibroin [118] 4-Arm-PEG-SH, tannic acid, Fe3+ complex [119] Chitosan, poly{2,5-thiophen-co-[3,6-di(thiophen-2yl)-2,5-bis(N,N,N-trimethylhexan-1-aminium)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione]-bromideco-4,7-(2,1,3-benzothia-diazole)} Antibacterial wound therapy [120] PEG diacrylate, polyoxometalate, 2,2′-azobis[2-(2-imidazolin-2-yl) propane] dihydro-chloride [121] Chitosan, CaO2nanoparticles, MnO2nanosheets [122] Catechol functionalized chitosan, MnO2nanosheets [123] Agarose, tannic acid-Fe nanoparticles [124] Gelatin, Cu2+ nanoparticles [125] Hyaluronic acid, Fe3+-EDTA complexes [126] Pharmaceutics 2025,17, 215 17 of 47 5.2.2. Temperature-Responsive Hydrogels These hydrogels expand or contract according to temperature variations, which is particularly advantageous for delivering drugs to inflamed or diseased tissues where local temperature can be elevated [ 127 – 130 ]. For example, temperature-sensitive hydrogel might remain stable at room temperature but swell upon encountering body temperature, thereby initiating drug release at the site of inflammation. Tunning the hydrogels’ composition and degree of crosslinking, it is possible to design ad hoc systems that respond predictably at physiological or pathological temperatures, ensuring efficient release with minimal secondary effects. The mechanism of thermal-triggered drug release is based on the polymer’s lower critical solution temperature (LCST) or upper critical solution temperature (UCST) [ 130 , 131 ]. The hydrogel undergoes a phase transition, altering its structure and permeability and disrupting the encapsulation environment, leading to a controlled burst or sustained release. Injectable thermosensitive hydrogels are an important subclass, as they transition from liquid to gel upon reaching physiological temperatures, allowing for minimally invasive administration and in situ drug release [ 132 , 133 ]. An example was given by M. Gou et al. [ 106 ], who prepared an injectable hydrogel from poly( ε -caprolactone)-PEG-poly( ε -caprolactone). It undergoes a sol–gel transition at physiological temperature, forming a nonflowing gel that allowed for the sustained release of hydrophobic drugs like honokiol. Similarly, Sim et al. [ 107 ] described the synthesis of a thermosensitive injectable hydrogel based on heparin-bearing poly( ε -caprolactoneco-lactide)-b-PEG-b-poly( ε -caprolactone-co-lactide). This hydrogel, designed for protein delivery, transitions from sol to gel at body temperature. It allowed for sustained release of proteins like lysozyme and exhibited excellent biocompatibility and minimal cytotoxicity in vivo . Liang et al. [ 108 ] described a methylcellulose/alginate hydrogel that combined temperature-sensitive methylcellulose with alginate, forming a gel at body temperature for protein drug delivery. It demonstrated effective site-specific release of bovine serum albumin in response to physiological changes in pH and temperature. Another example is the use of thermosensitive poly(ether urethane) hydrogels with pH-sensitive mesoporous silica nanoparticles for dual-responsive localized delivery. It demonstrated fast gelation, tunable release rates, and enhanced drug targeting for localized therapies [ 109 ]. Yanev et al. [ 110 ] synthesized a thermosensitive biodegradable hydrogel for neurological disorders. Based on PEG, N-(2-hydroxypropyl) methacrylamide-mono/dilactate and thiolated hyaluronic acid, this hydrogel was designed for sustained protein release in brain applications, providing controlled delivery for up to three weeks. It is worth mentioning the development of temperature-sensitive hydrogels for cancer treatment. In this case, hydrogel sol–gel transition at physiological temperatures allows localized drug delivery for cancer treatments such as chemotherapy, photothermal therapy, and immunotherapy. It provides high local drug concentration and sustained release with minimal systemic toxicity [ 134 ]. Luo et al. [ 111 ] applied chitosan-based hydrogel for localized breast cancer therapy using triptolide-loaded nanostructures. It showed enhanced tumor suppression by combining pro-apoptotic and anti-angiogenesis effects. To combat the same disease, hydrogels obtained from chitosan and agarose loaded with graphene or graphene oxide combined localized drug delivery and photothermal effects to improve the efficacy of breast cancer treatment while minimizing side effects [ 112 ]. Also, combining chemo-photothermal therapy, hydrogel obtained from chitosan, and β -glycerin sodium phosphate containing glycyrrhetinic acid-modified graphene oxide was applied. The hydrogel demonstrated temperature-dependent drug release and strong antitumor effects in hepatocellular carcinoma [ 113 ]. Al Sabbagh et al. [ 114 ] developed a poloxamerbased hydrogel for local chemotherapy in colorectal cancer. This thermosensitive hydrogel integrated poloxamers with 5-fluorouracil. It ensured sustained drug release and improved Pharmaceutics 2025,17, 215 18 of 47 therapeutic outcomes with minimal systemic exposure. Table 2includes the examples previously described as temperature-responsive hydrogels, including materials used for their synthesis and their application. 5.2.3. Photo-Responsive Hydrogels These hydrogels release drugs in response to light exposure, typically ultraviolet (UV) or near-infrared (NIR) light, which provides precise spatial and temporal control over drug release. Photo-responsive hydrogels can be particularly useful in treating conditions such as cancers or localized infections, where targeted light application can trigger localized drug release directly on the lesion site, reducing off-target effects and improving treatment efficacy [10]. In addition to the advantages described of offering precise, effective, and minimally invasive treatments, the use of photo-responsive hydrogels also presents the possibility of multimodal therapies, one of the most prominent options in the current treatment of cancer. In this sense, using polydopamine and alginate as the outer layer and gelatin as the core, fibers obtained by 3D printing allowed for localized and controlled drug release triggered by NIR light, ideal for postsurgical cancer treatment [ 10 ]. Z. Zhang et al. [ 115 ] developed a photosensitive hydrogel based on silk sericin and chitosan for breast cancer. This hydrogel, encapsulating ROS-sensitive tegafur and protoporphyrin IX, combined photodynamic therapy and chemotherapy. It offered on-demand drug release triggered by NIR light, maximizing therapeutic effects while reducing toxicity. P.-P. He et al. [ 116 ] prepared a hydrogel that integrates DNA and Ti3C2Tx-based MXene (atomically thin layers of transition metal carbides, nitrides, or carbonitrides) also for NIR-triggered photothermalchemo synergistic therapy. Under NIR light, it undergoes a gel-to-solution transition, releasing doxorubicin for efficient localized cancer therapy while reforming the gel matrix upon light removal [ 117 ]. Photothermal agarose hydrogel incorporating manganese oxide nanoparticles and chlorin e6 relieved tumor hypoxia and enabled NIR-induced photothermal and photodynamic therapies for enhanced tumor ablation. A Silk fibroin hydrogel was synthetized by S. Gou et al. [ 118 ]. This multistimuli-responsive injectable hydrogel released drugs like DOX upon NIR-triggered gel–sol transition. It combined chemo, photothermal, and photodynamic therapies to eliminate tumor masses and extend survival time in tumor-bearing mice. X. Zhu et al. [ 119 ] developed a 4-arm-PEG-SH injectable hydrogel, cross-linked with tannic acid and Fe 3+ complexes, which exhibited intrinsic NIR absorption for synergistic photothermal-chemotherapy and provided enhanced drug uptake and tumor ablation with excellent biocompatibility. For the treatment of localized infections, an intelligent hydrogel was synthetized integrating pH-sensitive bromothymol blue and NIR-absorbing conjugated polymers, poly{2,5thiophen-co-[3,6-di(thiophen-2-yl)-2,5-bis(N,N,N-trimethylhexan-1-aminiu-m)pyrrolo[3,4c]pyrrole-1,4(2H,5H)-dione]-bromide-co-4,7-(2,1,3-benzothia-diazole)}, into a thermosensitive matrix based on chitosan. It enabled visual diagnosis of bacterial infections and photothermal eradication of Staphylococcus aureus biofilms, making it effective against a broad range of bacteria, including drug-resistant strains [ 120 ]. Q. Li et al. [ 121 ] prepared a hydrogel using PEG diacrylate as a matrix, polyoxometalate as an acidity-enhanced photothermal agent and 2,2 ′ -azobis[2-(2-imidazolin-2-yl) propane] dihydro-chloride as thermo-responsive initiator. This hydrogel leveraged NIR light to initiate gelation and provide localized photothermal and thermodynamic antibacterial therapy. It was designed for non-antibiotic treatment of subcutaneous infections, targeting resistant bacteria with minimal systemic side effects. Incorporating MnO 2 nanosheets and CaO 2 nanoparticles, an alginate-based hydrogel generated oxygen to alleviate biofilm hypoxia and enhance photodynamic antibacterial activity. It effectively eradicated bacterial biofilms and pro- Pharmaceutics 2025,17, 215 19 of 47 moted healing in infection models [ 122 ]. Manganese oxide nanoparticles were also applied for the preparation of injectable hydrogel, combining redox and light responsiveness for treating multidrug-resistant bacteria and healing infected wounds. It delivered photothermal hyperthermia and sustained drug release, significantly accelerating wound healing while battling bacterial infections [ 123 ]. Also incorporating nanoparticles, Deng et al. [ 124 ] described agarose-based photothermal hydrogel containing tannic acid-Fe 3+ nanoparticles, creating an eco-friendly hydrogel with near-total bacterial eradication with exposure to NIR light. It demonstrated excellent in vitro and in vivo antibacterial activity, aiding in the treatment and healing of wound infections. Combining copper nanoparticles for photothermal conversion and sustained Cu 2+ ion release to combat both Gram-positive and Gram-negative bacteria, the gelatin-based hydrogel proposed by B. Tao et al. [ 125 ] accelerated healing in infected wounds while reducing inflammation and promoting angiogenesis. Using CuS nanoparticles, the hydrogel obtained from hyaluronic acid and Fe 3+ -EDTA complexes combined chemodynamic therapy and low-temperature photothermal therapy for infected wounds; it sterilized effectively while minimizing tissue damage, supporting robust healing [ 126 ]. Table 2includes the examples previously described as photo-responsive hydrogels, including materials used for their synthesis and their application. 5.2.4. Magnetically Responsive Hydrogels By embedding magnetic nanoparticles into a hydrogel matrix, they can respond to external magnetic fields, allowing for noninvasive, remote controlled drug release. This approach has shown promise in delivering drugs to deep tissues or specific organs, where the magnetic field can guide the hydrogel to the target site and initiate drug release through localized heating or structural changes induced by the field [ 21 ]. For these reasons, this is one of the most investigated approaches for the treatment of cancer. In this sense, different hydrogels have been investigated for the sustained release of doxorubicin. For example, dextran microgels with embedded Fe 3 O 4 nanoparticles exhibited dual responsiveness to pH and magnetic fields. These hydrogels enabled the controlled release of doxorubicin [ 135 ]. Similarly, a biocompatible silk fibroin hydrogel integrating Fe 3 O 4 nanoparticles was designed for sustained doxorubicin release under magnetic fields, reducing systemic toxicity [ 136 ]. A hydrogel based on alginate, gelatin, and Fe 3 O 4 nanoparticles demonstrated pH-dependent release of doxorubicin, making them ideal for localized chemotherapy [ 137 ]. Cao et al. [ 138 ] prepared a hydrogel combining poly(N-isopropylacrylamide) and alginate with graphene oxide and Fe 3 O 4 nanoparticles. It releases doxorubicin upon exposure to magnetic fields, light, and pH changes, offering controlled drug delivery for cancer therapy. Dai et al. [ 139 ] described a catechol–metal coordinated nanocomposite hydrogel. This hydrogel used dopamine-conjugated hyaluronac crosslinked with Fe 3 O 4 nanoparticles. It allowed on-demand, magnetic field-triggered release of doxorubicin for combination chemo-hyperthermia cancer therapy. Or a hydrogel based on tragacanth gum and acrylic acid-based hydrogel used Fe 3 O 4 nanoparticles to release doxorubicin in response to environmental triggers [ 140 ]. However, other active principles have also been delivered. For example, the tragacanth gum, N-isopropylacrylamide, and 3-(trimethoxysilyl) propylmethacrylate hydrogel incorporating Fe 3 O 4 nanoparticles delivered anticancer drugs like methotrexate with enhanced magnetic responsiveness [ 141 ]. Carboxymethyl cellulose/ β - cyclodextrin/chitosan hydrogels loaded with Fe 3 O 4 magnetic nanoparticles demonstrated pH-sensitive methotrexate release, with enhanced release under acidic conditions. This makes them suitable for targeted delivery in tumor environments [142]. The use of magnetic field-sensitive hydrogels has also been widely investigated for wound healing because of their capacity to selectively locate and deliver drugs. P. Wang et al. [ 143 ] developed a hydrogel combining cobalt ferrite nanoparticles with polyvinyl alcohol, using tannin as a bridging agent. It responded to static magnetic field, Pharmaceutics 2025,17, 215 20 of 47 enhancing cell adhesion, proliferation, antibacterial activity, and angiogenesis, thereby accelerating wound healing. Integrating MXene-wrapped magnetic Fe 3 O 4 @SiO 2 nanoparticles, this poly(N-isopropyl acrylamide)-alginate dual-network hydrogel delivered drugs in a photoand magnetoresponsive manner. It reduced drug toxicity and promoted the healing of deep chronic wounds, as demonstrated in full-thickness and infected wound models [ 144 ]. Using Fe 3 O 4 -based magnetic microspheres from natural polysaccharides, the chitosan-cellulose hydrogel prepared by Z. Wang et al. [ 145 ] offered self-healing, thermal reversibility, and controlled drug release. It was effective for delivering drugs in wound healing applications while maintaining mechanical stability. The starch-based hydrogel proposed by Nezami et al. [ 146 ] incorporated Fe 3 O 4 nanoparticles and itaconic acid grafted onto starch, enabling pH-sensitive and magnetically enhanced drug release. It was highly effective in wound healing and demonstrated a controlled release of guaifenesin. But the use of magnetically responsive hydrogels is not reduced to cancer treatment or wound healing. Examples of magnetic-responsive hydrogels are also found for the treatment of neurological disorders [ 147 ]. In this sense, injectable alginate hydrogel with magnetic short nanofibers for neural regeneration was described by Ghaderinejad et al. [ 148 ]. This hydrogel was composed of alginate incorporating magnetic polycaprolactone short nanofibers containing superparamagnetic iron oxide nanoparticles. It demonstrated the ability to align fibers under an external magnetic field, promoting neural differentiation and enhancing the bioactivity of encapsulated olfactory ecto-mesenchymal stem cells. This hydrogel showed promise as a minimally invasive scaffold for neural tissue repair. The system designed by Kang et al. [ 149 ] utilized a thermosensitive injectable hydrogel based on poly(lactic acid-ethylene glycol-lactic acid) incorporating drug-loaded micelles and water-dispersible ferrimagnetic iron oxide nanocubes. After injection into a resected glioblastoma site, the hydrogel gelated at body temperature, serving as a deep intracortical drug reservoir. Magnetic fields induced hyperthermia and enhanced drug diffusion, effectively targeting residual glioblastoma cells. This approach demonstrated significantly suppressed tumor growth and improved survival in a mouse model of glioblastoma. However, the investigation of magnetic-responsive hydrogels is currently so widely spread in the scientific community that other different applications can be found in the literature. For example, Bao et al. [ 150 ] described a chitosan/ β -glycerophosphate hydrogel loaded with superparamagnetic iron oxide nanoparticles to provide magnetic stimulation for the repair of the vagus nerve. Under a mild magnetic field (~100 mT), it reduced heart rate and improved vagus nerve activity. Four weeks of magnetic stimulation (20 Hz, 5 min, three times daily) post-myocardial infarction significantly enhanced cardiac function, reduced infarct size, and suppressed inflammation in myocardial infarction models in rats, demonstrating promising noninvasive treatment for myocardial infarction. Mahdavinia et al. [ 151 ] designed a carboxymethyl cellulose/montmorillonite hydrogel for colon targeting. This magnetic nanocomposite hydrogel, incorporating carboxymethyl cellulose, acrylamide, N,N ′ -methylene bis acrylamide (as crosslinking agent) and magnetic (Fe 3 O 4 ) montmorillonite, was designed for colon-specific drug delivery. It released diclofenac effectively in response to pH and magnetic field stimuli, targeting localized drug delivery in the gastrointestinal tract. Liposomes loaded with ferulic acid were included in magnetic gelatin hydrogels also containing Fe 3 O 4 magnetic nanoparticles. It enabled precise, magnetically modulated drug release, suitable for cell development and faster tissue regeneration [152]. In summary, the development of smart hydrogels has transformed the landscape of drug delivery by enabling controlled, targeted, and personalized treatment options. As research advances, new types of stimuli-responsive hydrogels continue to emerge, offering exciting possibilities for future therapeutic applications. Table 3includes the examples Pharmaceutics 2025,17, 215 21 of 47 previously described as magnetically responsive hydrogels, including materials used for their synthesis and their application. Table 3. Summary of magneticallyand redox-sensitive hydrogels, including materials used for their synthesis and their application. Stimuli Materials Applications Ref. Magnetically Responsive Dextran, Fe3O4nanoparticles Improving doxorubicin treatment (Cancer therapy) [135] Silk fibroin, Fe3O4nanoparticles [136] Gelatin, alginate, Fe3O4nanoparticles [137] Poly(N-isopropylacrylamide), alginate, graphene oxide Fe3O4nanoparticles [138] Dopamine-conjugated hyaluronac crosslinked with Fe3O4nanoparticles [139] Tragacanth gum, acrylic acid Fe3O4nanoparticles [140] Tragacanth gum, N-isopropylacrylamide, 3-(trimethoxysilyl) propylmethacrylate, Fe3O4nanoparticles Improving methotrexate treatment (Cancer therapy) [141] Carboxymethyl cellulose, β -cyclodextrin, chitosan, Fe3O4nanoparticles [142] Polyvinyl alcohol, cobalt ferrite nanoparticles Wound healing therapy [143] Poly(N-isopropyl acrylamide), alginate, MXene-wrapped Fe3O4@SiO2 nanoparticles [144] Chitosan, cellulose, Fe3O4nanoparticles [145] Starch, itaconic acid, Fe 3 O 4 nanoparticles, guaifenesin [146] Alginate, polycaprolactone, Fe3O4 nanoparticles Neurological disorders management [148] Poly(lactic acid-ethylene glycol-lactic acid), Fe3O4nanocubes [149] Chitosan, β-glycerophosphate, Fe3O4 nanoparticles Myocardial infarction management [150] Carboxymethyl cellulose, acrylamide, N,N′-methylene bis acrylamide, Fe3O4-containing montmorillonite, diclofenac Colon drug delivery [151] Gelatin, liposomes loaded with ferulic acid, Fe3O4nanoparticles Cell development and faster tissue regeneration [152] Redox-Responsive PEG-based polymers, pyridyl disulfide Bovine serum albumin delivery [153] Bis(2-methacryloyloxyethyl) disulfide, PEG, 2-(diisopropylamino) ethyl methacrylate Tumor growth control Cancer Immunotherapy [154] Calcium selenite/L-arginine nanospheres, Glucose oxidase, 6-aminonicotinamide, Sodium alginate [155] Calcium phosphate, Polyacrylic acid, ROS-sensitive MnO2[156] ε-Polylysine, pluronic F127, MnO2 nanosheets Wond healing in diabetes [157] Graphene derivates, cerium oxide nanoparticles Neural stem cell regeneration [158] 5.2.5. Redox-Responsive Systems Redox-responsive have been studied to utilize the intracellular redox environment, such as NADP + /NADPH, O 2 / O− 2 and glutathione (GSH)-reduced glutathione (GSSG), particu- Pharmaceutics 2025,17, 215 22 of 47 larly the enhanced levels of GSH in cancer cells, 4–5 times higher than normal ones [ 159 ]. This pH imbalance, added to the presence of disulfide linkage within the polymer structure, gives the prospect of selective drug release in such redox-active locales. An example of a redox-sensitive hydrogel using the thiol-disulfide exchange method was reported by Kilic Boz et al. [ 153 ], who developed linear telechelic PEG-based polymers combined with pyridyl disulfide units and thiol-terminated tetraarm PEG polymers. This resulted in the formation of macroporous hydrogels with high water absorption (>85%), and self-healing because of disulfide linkages. These hydrogels disintegrated in thiol-containing environments such as GSH, enabling the controlled release of bovine serum albumin. Cytocompatibility tests verified their suitability for biological drug delivery purposes, allowing drug release as needed. D. Huang et al. [154] produced microgels that were sensitive to redox environments by combining bis(2-methacryloyloxyethyl) disulfide, PEG, and 2-(diisopropylamino) ethyl methacrylate. The microgels inhibited tumor cell proliferation in vitro and reduced tumor growth in living organisms, showing potential for treating cancer. Based on the NADP + /NADPH, W. Tao et al. [ 155 ] created a hydrogel containing calcium selenite/L-arginine nanospheres, glucose oxidase, and 6-aminonicotinamide in sodium alginate. The selenite and 6aminonicotinamide synergistically triggered intracellular NADPH exhaustion by promoting cystine metabolism-mediated NADPH consumption and inhibiting NADPH generation, respectively. This injectable hydrogel formed under natural conditions stimulated immunogenic cell death in tumor cells by increasing reactive oxygen species (ROS) and reactive nitrogen species (RNS). Robby et al. [ 156 ] developed a O 2 / O− 2 responsive system. The incorporation of ROS-sensitive MnO 2 initially suppressed the calcium phosphate mineralization of polyacrylic acid via carboxyl-Ca 2+ complexation. In the presence of elevated ROS levels typically found in cancer cells, the MnO 2 was cleaved into Mn 2+ ions, triggering the mineralization process and leading to the formation of a PAA-MnO 2 mineralized hydrogel. In vivo studies conducted on tumor-bearing mice demonstrated that the PAA-MnO 2 hydrogel effectively formed at tumor sites, mainly due to its robust ROS-scavenging capabilities. Similarly, a novel hydrogel was prepared by S. Wang. et al. [ 157 ] involving MnO 2 nanosheets coated with ε -polylysine and insulin-loaded micelles formed by self-assembled aldehyde Pluronic F127. Taking advantage of the combined effects of ε -polylysine and the “nanoknife-like” structure of MnO 2 nanosheets, the resulting hydrogel demonstrated remarkable antimicrobial efficacy against multidrug-resistant bacteria. Furthermore, the MnO 2 nanoenzyme effectively modulated the oxidative wound microenvironment by catalyzing the conversion of endogenous H 2 O 2 into O 2 . Simultaneously, the pHand redox-responsive hydrogel facilitated the controlled, sustained, and localized release of insulin, contributing to blood glucose regulation. Polo et al. [ 158 ] prepared a hydrogel integrating graphene derivatives and cerium oxide nanoparticles, forming a three-dimensional scaffold that enhanced neural stem cell adhesion, migration, and differentiation. It supported the differentiation of neural stem cells into neuronal, astroglial, and oligodendroglial cells, providing a promising platform for neural tissue engineering and regenerative therapies. Table 3includes the examples previously described as redox-responsive hydrogels, including materials used for their synthesis and their application. 5.2.6. Enzyme-Triggered Systems Enzyme-sensitive hydrogels represent a versatile and innovative tool for controlled drug delivery as a result of their ability to respond specifically to enzymatic activity in targeted environments. These hydrogels leverage the elevated expression or activity of specific enzymes, such as matrix metalloproteinases (MMPs), glucose oxidase (GOx), alkaline phosphatase (ALP), hyaluronidase or β -galactosidase, often associated with pathological conditions like cancer or inflammation. This precise responsiveness allows the release of therapeutic agents only when and where needed, minimizing systemic side effects and Pharmaceutics 2025,17, 215 23 of 47 enhancing therapeutic efficacy [ 160 ]. Moreover, enzyme-sensitive hydrogels can incorporate labile linkages or crosslinks that selectively degrade in the presence of overexpressed enzymes in diseased tissues, such as tumor microenvironments, enabling localized and on-demand drug release [ 161 ]. Their biodegradability, biocompatibility, and ability to respond under mild physiological conditions further make them ideal candidates for DDSs in sensitive therapeutic scenarios [ 162 ]. These advantages highlight the potential of enzymesensitive hydrogels to revolutionize targeted therapies, especially in cancer treatment and regenerative medicine. As mentioned above, hydrogels that respond to different specific enzymes have been developed. Hydrogels sensitive to glucose have demonstrated significant utility in the preparation of specific self-regulating liberation systems. GOx is able to convert glucose into gluconic acid [ 160 ]. This pH decrease triggers the release of insulin from pH-responsive hydrogels. As an example, hydrogels synthesized from N,N-diethylaminoethyl methacrylate and 2-hydroxypropyl methacrylate, crosslinked with a polyacrylamide membrane immobilizing GOx, have shown promising results [ 163 ]. Low pH membrane induced protonation of amino groups causing drug release, leading to hydrogel expansion and increasing permeability of membrane to insulin. Similarly, concanavalin A is a natural carbohydrate-binding protein and forming a tetrameric structure that can bind to four glucose molecules, acting as a macromolecular crosslinker. D. Dong et al. [ 164 ] developed Cu 2 O/Pt hydrogels through the mixture of Cu 2 O/Pt nanocubes with alginate and hyaluronic acid. The hydrogel utilized GOx to convert glucose, producing gluconic acid while decreasing the pH in the wound site. In acidic conditions, Cu 2 O/Pt nanocubes react with H 2 O 2 to release hydroxyl radicals, which leads to antibacterial effects through ROS-based mechanisms. Cu ions released from the hydrogel also enhance the expression of vascular endothelial growth factor, leading to the stimulation of endothelial cell proliferation and angiogenesis, both essential for wound healing. In vivo studies conducted on diabetic rats infected with S. aureus showed that the Cu 2 O/Pt hydrogel sped up wound healing, raised epithelial thickness, and improved the regeneration of hair follicles and sebaceous glands. Xian et al. [ 165 ] developed a hydrogel for glucose monitoring and insulin delivery. It consisted of a glucose oxidase-responsive hydrogel based on phenylboronic acids and diols that integrated dynamic covalent crosslinking to enable insulin release in response to glucose levels. It offered a stable and injectable platform to manage blood glucose with minimal daily interventions. Concanavalin A can be integrated into the hydrogel matrix and can release insulin depending on glucose levels [ 166 ]. K. Lin et al. [ 167 ] created a hydrogel that responds to glucose, using pullulan and modifying concanavalin A covalently derivative with COOH groups, enabling smart and regulated insulin release with changes in levels of glucose. The hydrogel expands and discharges insulin upon stimulation. Elevated glucose levels lead to increased insulin release; however, insulin release decreases when glucose levels are low. But some other enzyme-sensitive hydrogels have been developed to deliver active principles different from insulin and using a different strategy. MMPs are a group of endopeptidases capable of breaking peptide bonds. They are involved in adhesion, survival, proliferation and differentiation, migration, and intercellular interactions, among other functions. Tumor cells secrete MMPs and other proteolytic enzymes into the extracellular matrix to degrade its components and facilitate tumor growth. High MMP activity, particularly in tumor tissues, makes these enzymes ideal as biological triggers for enzyme-responsive anticancer DDSs [ 160 ]. Based on the response to these enzymes, C. Cai et al. [ 168 ] developed a hydrogel consisting of carboxymethyl chitosan with MMP-2 as crosslinker and polycaprolactone. This hydrogel was designed to form electrospun fibers to release siRNA in response to MMP-2 activity. This system presented a unidirectional design to avoid interference in tissues such as tendons, Pharmaceutics 2025,17, 215 24 of 47 effectively inhibiting fibroblast proliferation, reducing tendon adhesions, and silencing fibrosis gene transforming growth factorβ 1, thus reducing side effects in sensitive tissues. W. Chen et al. [ 169 ] synthesized an MMP-2/9-responsive hydrogel system based on tetraPEG that delivered therapeutic factors (carbon dots coupled with interleukin-4 plasmid DNA) to regulate the immune microenvironment after myocardial infarction. The hydrogel responded to MMP activity in injured tissue, triggering the release of encapsulated agents, which reduced inflammation and improved cardiac repair. Systems sensitive to MMP-13 were described by T. Zhou et al. [ 170 ], who prepared a hydrogel microsphere system to treat osteoarthritis by combining ROS scavenging, MMP-13 sensitivity, and hypoxia-responsive drug release. The system used sulfonated azocalix[4]arene as a host molecule to load the anti-inflammatory drug hydroxychloroquine, forming a host–guest complex that synergistically reduces inflammation. Sulfonated azocalix[4]arene was modified with a methacryloyl group to create a covalently crosslinked hydrogel network with methacrylated hyaluronic acid. An MMP-13-sensitive peptide with thiol groups was incorporated into the hydrogel, enabling on-demand drug release and degradation in response to overexpressed MMP-13 in the osteoarthritis microenvironment, to alleviate disease progression. ALP is an enzyme found throughout the body that catalyzes the hydrolysis of phosphate esters at an alkaline pH (optimal around pH 8–10). This enzymatic activity results in the release of inorganic phosphate and alcohol from the substrate through a coordinated process facilitated by metal ions and nucleophilic catalysis. This enzymatic activity results in the release of inorganic phosphate and alcohol from the substrate through a coordinated process facilitated by metal ions and nucleophilic catalysis [ 171 , 172 ]. ALP is crucial in several physiological processes, including bone mineralization, lipid transport, and cellular signaling. By breaking down pyrophosphate, a natural bone mineralization inhibitor, ALP facilitates hydroxyapatite deposition in bones, which forms the basis for its use in treating hypophosphatasia [ 171 , 172 ]. Additionally, ALP’s ability to detoxify lipopolysaccharides by dephosphorylation highlights its anti-inflammatory properties, making it a promising therapeutic for sepsis, inflammatory bowel disease, and acute kidney injury by reducing systemic inflammation. Its phosphatereleasing activity further contributes to tissue regeneration and wound healing, where ALP promotes mineral formation for bone repair. Therefore, ALP’s responsiveness to phosphate substrates is also exploited in the development of ALP-sensitive hydrogels [ 173 , 174 ]. In this sense, N. Li et al. [ 175 ] developed a chitosan membrane incorporating a responsive hydrogel to ALP for the treatment of periodontitis. This hydrogel was prepared from phosphorylated polyester (polyphosphoester-b-PEG-b-polyphosphoester) and minocycline hydrochloride, releasing antibiotic and osteogenic drugs in response to ALP activity. Studies demonstrated that drug release in vitro / in vivo from this membrane enhanced osteogenesis and periodontal treatment when it comes to fighting infection. Y. Gao et al. [ 176 ] created a prodrug by combining paclitaxel with the phosphorylated peptide, taking advantage of ALP found in high levels in cancer cells to activate the drug in a specific location. ALP removed the phosphate group from the inactive drug, turning it into a substance that formed a hydrogel at the affected area. This allowed the controlled and continuous release of medication. This approach significantly boosted paclitaxel’s ability to dissolve in a significant way, all while keeping its effectiveness in fighting tumors, bringing together the transportation of the drug and its therapeutic effects within one single molecule. The method offered a worldwide strategy for administering hydrophobic medications with increased accuracy and decreased overall side effects. Hyaluronidases are a group of enzymes that catalyze the breakdown of hyaluronic acid (HA), a major component of the extracellular matrix (ECM), into smaller fragments. Hyaluronidases cleave HA through hydrolysis (hyaluronan degradation), resulting in decreased viscosity and improved permeability within tissues. Hyaluronidase-sensitive hydrogels have special relevance in cancer therapy. They degrade selectively in the tumor microen- Pharmaceutics 2025,17, 215 25 of 47 vironment where hyaluronidase expression is upregulated, allowing localized delivery of chemotherapeutic agents. For example, Fiorica et al. [ 177 ] described a HA/cyclodextrin-based injectable hydrogel for local doxorubicin delivery to solid tumors. In vitro studies demonstrated that the unique physicochemical characteristics of the hydrogel ensure a prolonged release of doxorubicin, effectively inhibiting the growth of colorectal carcinoma micromasses cultured under 3D conditions. In vivo experiments further validated the hydrogel’s efficacy, showing a significant reduction in tumor mass within the animal model while avoiding cytotoxic effects in nontarget organs. Vildanova et al. [ 178 ] prepared biodegradable hydrogels based on chitosan and pectin for the delivery of cisplatin. The prolonged release of cisplatin was shown to be dependent on the polymers’ concentrations. In any case, the degradability of the hydrogels in the presence of hyaluronidase enhanced drug delivery specifically in tumor microenvironments, where hyaluronidase activity is elevated. But other applications have been explored. For wound healing, Hong et al. [ 179 ] synthesized a hemostatic adhesive hydrogel that effectively controlled bleeding and minimizes abnormal tissue adhesion following hemostasis. A photo-crosslinked hydrogel was developed using methacrylatemodified gelatin and N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy) butanamide conjugated to hyaluronic acid. This hydrogel exhibited outstanding mechanical strength and tissue adhesion properties, enabling rapid hemostasis. Upon UV photoactivation, the hydrogel polymerized and adhered within seconds, creating a robust bond to wet biological tissue surfaces. The action of hyaluronidases could also be explored for tissue engineering. For example, S. Zhou et al. [ 180 ] prepared an injectable, self-healing, and multiple responsive histamine-modified hyaluronic acid hydrogel. The presence of the imidazole moiety allowed a dynamic coordinative bonding with metal ions. Using Zr 4+ , the obtained hydrogel presented responsiveness when exposed to a weak alkaline environment and hyaluronidase, inhibiting bacterial growth and biofilm formation. This behavior highlights this hydrogel as an implantable material for tissue engineering. Table 4includes the examples previously described as enzyme-responsive hydrogels, including materials used for their synthesis, the enzymes to which they are sensitive and their application. Table 4. Summary of enzyme-sensitive hydrogels, including materials used for their synthesis, the enzymes to which they are sensitive and their application. Stimuli Materials Enzime Sensitivity Applications Ref. Enzyme-Triggered N,N-Diethylaminoethyl methacrylate, 2-hydroxypropyl methacrylate, GOx GOx Insulin release and diabetes management Diabetes management [163] Cu2O/Pt nanocubes, alginate, hyaluronic acid, GOx [164] Phenylboronic acids, diols, GOx [165] Modified Concanavalin A, pullulan, GOx [167] Carboxymethyl chitosan, polycaprolactone, MMP-2 MMP Tissue regeneration [168] Tetra-PEG-based hydrogel, carbon dots coupled with interleukin-4 plasmid DNA Cardiac repair [169] Methacryloyl sulfonated azocalix[4]arene, methacrylated hyaluronic acid Osteoarthritis treatment [170] Phosphorylated polyester, minocycline hydrochloride. ALP Periodontal treatment [175] Phosphorylated peptide, paclitaxel Cancer treatment [176] Hyaluronic acid, cyclodextrin, doxorubicin Hyaluronidase Colorectal carcinoma treatment [177] Chitosan, pectin, cisplatin. Sensitive to hyaluronidases Cancer therapy [178] Gelatin, N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2methoxy-5-nitrosophenoxy) butanamide, hyaluronic acid. Sensitive to hyaluronidases Wound healing [179] Histamine-modified hyaluronic acid crosslinked with Zr4+. Sensitive to hyaluronidases Inhibition bacterial growth and biofilm formation [180] Pharmaceutics 2025,17, 215 32 of 47 chemo/hyperthermia therapy, demonstrating significant doxorubicin loading efficiency and controlled release under magnetic and reductive conditions. Similarly, Massoumi et al. [ 214 ] synthesized a Fe 3 O 4 -loaded nanogel based on the copolymerization of N-isopropylacrylamide, maleic anhydride and starch. The system showed an optimized release of doxorubicin against both thermal and pH stimuli. These studies collectively underscore the versatility and efficacy of magnetic-responsive nanogels in advancing targeted drug delivery and combination therapies for cancer treatment. Another noteworthy application is in antimicrobial therapy. F. Gao et al. [ 215 ] developed multifunctional magnetic nanogels incorporating Fe 3 O 4 nanoparticles and cationic poly(2-(dimethylamino)-ethyl methacrylate, demonstrating broad-spectrum antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans. This system presented special promise not only in tackling bacterial infection but also in stimuli-responsive applications such as protein adsorption and separation. 6.3.5. Redox-Responsive Release Similarly to macroor micro-hydrogels, nanogels can be designed to be redoxresponsive; therefore, they can respond to NADP + /NADPH, O 2 / O− 2 , or GSH-GSSG systems, among others, in higher concentrations in the intracellular environment. However, most of the redox-sensitive nanogels are designed to respond to GSH. Using this principle, Y. Wang et al. [ 216 ] discussed a redox-responsive system using disulfide bonds for GSH-triggered drug release. Polyethylene glycol was conjugated to poly(amidoamine) dendrimers via disulfide bonds, and cyclo(Arg-Gly-Asp-d-Phe-Cys) peptides were added to enhance targeting to integrin-overexpressed tumor cells. Doxorubicin release was triggered by elevated GSH levels within the tumor microenvironment. S. Wang et al. [ 218 ] prepared a lentinan-based nanogel using a disulfide-containing crosslinker to load diosgenin for chemo-immunotherapy. This nanogel inhibited the proliferation and metastasis of lung cancer cells. In addition, it promoted the proliferation of dendritic cells, increased the production of NO, and upregulated the expressions of the costimulatory molecules CD40, CD80, CD86, and MHC-II major histocompatibility complex class II due to the release of lentinan. Instead of including disulfide bond in the polymer chain, Tian et al. [ 217 ] developed diselenide-crosslinked zwitterionic nanogels with dual redox-labile properties under oxidative (H 2 O 2 ) or reducing (GSH) conditions. These nanogels were prepared from 2-methacryloyloxyethyl phosphorylcholine and a diselenide bond-containing crosslinker and loaded with doxorubicin, showing a significant inhibitory effect against tumor cells. 6.3.6. Enzyme-Responsive Release Also, making use of the selectivity of enzymes against certain biomolecules, nanogels have been developed as enzyme-responsive systems. An example of enzyme-responsive nanogels based on the response to GOx was described by D. Zhou et al. [ 219 ], who prepared polymersomes from N,N-diethylaminoethyl methacrylate and 2-hydroxypropyl methacrylate incorporating GOx, as a glucose and pH dual responsive with multilevel self-regulation of blood glucose for insulin delivery. Using the capacity of GOx to convert glucose in glucuronic acid, the membrane permeability changed due to the protonation of amino groups at low pH, facilitating controlled insulin release. The system leverages pH sensitivity to regulate drug delivery in response to local acidic environments, such as inflammation or hyperglycemic conditions. As examples of MMT-sensitive systems, Massi et al. [ 220 ] described peptide-crosslinked nanogels that degraded in response to MMP-7, an enzyme overexpressed in inflammatory diseases and cancers. The nanogels were engineered for temperature-sensitive protein delivery. MMP-7 cleaved specific peptide sequences, enabling enzyme-triggered nanogel disassembly and the release of encapsu- Pharmaceutics 2025,17, 215 33 of 47 lated therapeutic proteins. The nanogels were successfully loaded with model proteins and released their cargo in response to MMP-7 activity. Sensitive to MMP-9, Gordon et al. [ 221 ] designed derivatized (meth)acrylate-based nanogels, where MMP-9 cleaved specific peptide linkages, converting the surface of the nanogels from inactive to active properties to improve cellular uptake. This surface conversion enhanced their targeting ability in tumor microenvironments rich in MMP-9. These nanogels exhibited superior responsiveness to MMP-9, promoting greater uptake into cancer cells. Wu et al. [ 222 ] developed ALP-sensitive nanogels based on alginate-polyethyleneimine copolymers. The system successfully encapsulated and released doxorubicin in response to enzymatic triggers, where the nanogels were efficiently internalized by cells, demonstrated biocompatibility, and reduced cytotoxic effects compared to conventional carriers. Based on the action of hyaluronidases, J. Zhu et al. [ 223 ] developed a hybrid nanogel of aminoethyl methacrylate hyaluronic acid and methacrylated methoxy polyethylene glycol loaded with chlorhexidine for rapid hemostasis and antibacterial action, for wound healing. This nanogel presented low cytotoxicity and a prolonged release period of chlorhexidine, as well as rapid hemostasis capacity and accelerated wound healing in vivo using a mouse model. 7. Examples of FDA-Approved Hydrogels and Nanogels As previously discussed, hydrogels and nanogels are extensively utilized for drug delivery, wound healing, and cosmetic and therapeutic interventions, with several formulations approved by regulatory agencies such as the FDA, underscoring their clinical relevance (Table 6). In drug delivery applications, hydrogels such as Cervidil ® and Zuplenz ® exemplify the versatility of these systems. Cervidil ® , composed of a cross-linked hydrogel copolymer made from hexanetriol, macrogol 8000, and isocyanate, facilitates cervical ripening in pregnant women. This hydrogel provides localized and controlled release of dinoprostone, minimizing systemic side effects while mimicking natural tissue environments. Zuplenz ® , comprising polyvinyl alcohol, macrogol 1000, and rice starch, is designed for managing nausea and vomiting induced by chemotherapy, radiation, or postoperative procedures. Its advantage lies in its patient-friendly, non-invasive oral delivery route. Hydrogels also play a pivotal role in wound management. 3M Tegaderm ® , containing propylene glycol, is employed for low to moderate draining wounds, while DermaGauze ® , an acrylate polymer hydrogel, addresses acute and chronic partial-thickness wounds. These formulations maintain a moist wound environment conducive to re-epithelialization and enhanced healing. However, they may be less effective for heavily exuding wounds and can require frequent replacement, potentially increasing patient discomfort and cost. Injectable hydrogels, such as Teosyal ® , Belotero ® , and Infuse ® , highlight the adaptability of hydrogel systems in cosmetic and regenerative medicine. Teosyal ® and Belotero ® , both based on hyaluronic acid (Belotero ® also includes lidocaine for pain reduction), are widely used for correcting facial wrinkles and folds. Their biocompatibility, immediate cosmetic results, and reversibility are significant advantages. However, these benefits are offset by risks such as local injection site reactions and the need for repeated treatments due to biodegradation. Infuse ® , composed of collagen and recombinant human bone morphogenetic protein-2, is designed for use in spinal, oral, maxillofacial, and orthopedic surgeries. It effectively promotes bone regeneration, although complications such as ectopic bone formation and inflammatory responses have been reported. Regarding nanogels, Copaxone ® , a nanogel composed of L-glutamate, L-alanine, L-lysine, and L-tyrosine random copolymers, is used to treat multiple sclerosis, reducing relapse rates and improving outcomes. However, its immunogenic potential and subcutaneous administration can result in local injection site reactions. Zilretta ® , formulated with poly(lactic-co-glycolic acid) microspheres, delivers extended pain relief in osteoarthritis of the knee, reducing dosing frequency and improving Pharmaceutics 2025,17, 215 34 of 47 patient adherence. Renagel ® , a nanogel prepared from poly(allylamine hydrochloride), is used to manage hyperphosphatemia in chronic kidney disease by increasing circulation and therapeutic delivery. While effective, its gastrointestinal side effects and the high pill burden can pose adherence challenges. Table 6. Hydrogels and nanogels already approved by the FDA. Category Name Composition Approved Indication Year of Approval Reference Hydrogel for drug delivery Cervidil® Hexanetriol, macrogol 8000, isocyanate cross-linked hydrogel copolymer Initiation and/or continuation of cervical ripening in pregnant women at or near term 1993 [227] Hydrogel for drug delivery Zuplenz®Polyvinyl alcohol, macrogol 1000, rice starch Chemotherapy, radiation, and postoperativeinduced nausea and vomitin 1991 [228] Hydrogels for wound dressing 3M Tegaderm®Propylene glycol Low to moderate draining wounds, partial and full-thickness dermal ulcers 2018 [229] Hydrogels for wound dressing DermaGauze ®Acrylate polymer Acute or chronic partial and full thickness wounds 2014 [230] Injectable hydrogels Teosyal®Hyaluronic acid Filling of facial wrinkles and folds 2017 [230] Injectable hydrogels Belotero®Hyaluronic acid with lidocaine Moderate to severe facial wrinkles and folds 2019 [230] Injectable hydrogels Infuse® Collagen and recombinant human bone morphogenetic protein-2 Spine, oral, maxillofacial and orthopedic trauma surgeries 2002 [231] Nanogel for drug delivery Copaxone® L-Glutamate, L-alanine, L-lysine, L-tyrosine random copolymer Treatment of multiple sclerosis 1996 [232] Nanogel for drug delivery Zilretta®Poly(lactic-co-glycolic acid) matrix microspheres Extended pain relief over 12 weeks of osteoarthritis of the knee 2017 [233] Nanogel for drug delivery Renagel®Poly(allylamine hydrochloride) Increase circulation and therapeutic delivery in chronic kidney disease 2000 [234] 8. Challenges, Advanced Applications, and Future Strategies The development and application of advanced DDS have significantly transformed the area of Biomedicine in the last two decades, since more efficient, controlled, and targeted therapies for a variety of diseases have been carefully designed. Among the most promising materials, hydrogels and nanogels stand out due to their distinctive physical and chemical characteristics, such as their high water content, biocompatibility, and the capacity to encapsulate a broad spectrum of therapeutic moieties. Unfortunately, critical challenges including Pharmaceutics 2025,17, 215 35 of 47 scale-up production, regulatory approval processes, and the need for enhanced targeting and releasing mechanisms remain uncertain. Among the most promising future strategies to tackle these obstacles and to foster the use of hydrogels and nanogels for drug delivery applications with the aim of more personalized clinical treatment are the following groups: Advancements in material design and synthesis including tailored properties: one of the most critical areas to focus on is the design and synthesis of hydrogels and nanogels with tailored properties. Traditional hydrogels, often composed of synthetic or natural polymers, offer a broad range of properties, but to fully harness their potential for drug delivery, there is a need for more versatile and responsive materials. Interestingly, developing new smart and stimuli-responsive hydrogels or nanogels that can undergo reversible changes in their structure in response to external stimuli such as pH or temperature can significantly enhance the effectiveness of the release. Alternatively, the combination of hydrogels and nanogels may promote the advantages of each. For instance, biopolymers can improve stability, mechanical strength, and drug-loading capacity, which could be increased by incorporating nanoparticles into hydrogel networks to enhance the mechanical properties and loading efficiency. Advancements in the fabrication design: although some examples have been included in this literature review, not so many authors have explored the possibility of combining different hydrogels or nanogels to achieve a final global objective, not achievable by one single hydrogel. In addition, additive manufacturing, also known as 3D printing, offers the possibility of fabricating advanced hydrogels based on the manufacturing process advantages offered by this technology. In addition, the combination of 3D printing with stimuli-response materials paved the way for advanced additive manufacturing, called 4D printing. Targeted drug delivery through surface functionalization: to mitigate undesired secondary effects and systemic toxicity due to the lack of specificity in targeting diseased tissues, the surface functionalization with targeting moieties appears as a promising strategy. In this sense, ligand-based targeting based on ligands that incorporate antibodies, peptides, or small molecules that specifically bind to receptors and are overexpressed on target cells can improve the precision of drug delivery. Also, as an alternative functionalization with nanoparticles such as gold, silver, or magnetic nanoparticles can further enhance targeting for antibacterial or prosthesis applications. Also, more biomaterials such as polyethylene glycol (PEG) to avoid recognition and clearance by the immune system will be essential to develop in the near future to promote bioavailability. Advanced drug loading and release mechanisms: to match therapeutic needs the development of new polymer networks, including nanogels matrixes with high superficial areas, is convenient to achieve higher drug entrapment and stability. Also, systems that provide dual-stimuli-responsive systems that release the drug in stages are often needed in tumor tissues and usually are not so easy to design. The modulation of biodegradation to reach the target and ensure bioactivity could also be modulated on the basis of the chemical structure of the gels. Scale-up and manufacturing considerations: A major challenge in hydrogel and nanogel production is the development of scalable methods that ensure high quality, stability, and reproducibility. The transition from laboratory-scale synthesis to industrial-scale manufacturing requires addressing several technical and economic barriers. One of the most pressing issues is the high cost associated with the production of these materials. This includes the expense of raw materials, many of which are specialized polymers or biopolymers, as well as the energy-intensive nature of certain preparation methods, such as chemical crosslinking or advanced techniques like microfluidics and 3D printing. Furthermore, specialized equipment needed for precision synthesis and quality assurance adds Pharmaceutics 2025,17, 215 36 of 47 to the financial burden, particularly for small-scale manufacturers or academic spin-offs attempting to commercialize these technologies. To overcome these economic challenges, there is a pressing need to explore innovative approaches such as using cost-effective, biodegradable polymers, optimizing reaction conditions to reduce energy inputs, and adopting scalable green chemistry techniques that minimize resource consumption and waste generation. Another significant hurdle in scaling up hydrogel and nanogel production is the issue of batch-to-batch variability. Even minor deviations in the raw material quality, environmental conditions (such as temperature, pH, or humidity), or synthesis parameters (e.g., polymerization time and crosslinking efficiency) can result in inconsistencies in the physicochemical properties of the final product. Such variability can compromise therapeutic efficacy, biocompatibility, and stability, posing challenges for clinical applications and regulatory approval. For example, slight differences in polymer chain length, crosslinking density, or nanoparticle size distribution can significantly affect drug release profiles, bioavailability, and patient outcomes. To address these issues, advanced quality control and process optimization strategies are essential. Automation of production processes, coupled with real-time monitoring systems, can help ensure consistent control over critical synthesis parameters. Techniques such as inline spectroscopy, advanced chromatography, and machine learning algorithms for predictive quality analysis are emerging as valuable tools to identify and mitigate sources of variability. Additionally, robust standard operating procedures (SOPs) and adherence to good manufacturing practices (GMP) are critical for maintaining consistent quality across production batches. Moreover, regulatory requirements for hydrogels and nanogels intended for therapeutic use further emphasize the need for stringent quality control. The variability in production must be minimized not only to satisfy commercial scalability but also to meet the standards of regulatory bodies such as the FDA and EMA. These agencies often require extensive validation of reproducibility, biocompatibility, and long-term stability before approving materials for clinical use, making batch-to-batch consistency a critical aspect of successful commercialization. Future progress in addressing these challenges will likely involve integrating novel manufacturing technologies, such as continuous flow reactors, which offer enhanced control over reaction conditions and scalability. Additionally, leveraging modular microfluidic systems can enable precise particle size control and high-throughput production, thereby reducing variability and improving scalability. Combining these innovations with sustainable practices, such as recycling solvents and minimizing chemical waste, could further enhance the feasibility of hydrogel and nanogel manufacturing for widespread therapeutic applications. Regulatory challenges and clinical translation: while hydrogels and nanogels are widely regarded as biocompatible, their potential toxicity, long-term biodegradability, and immune responses require careful consideration, particularly for injectable applications. Toxicity may arise from residual monomers, crosslinking agents, or degradation by-products, which could accumulate in tissues or induce local cytotoxic effects. To minimize such risks, the use of non-toxic, FDA-approved materials and thorough purification protocols during synthesis is essential. Long-term biodegradability is another critical factor, as incomplete degradation or the formation of insoluble fragments could lead to accumulation and adverse effects. Materials designed with tunable degradation profiles, such as those based on naturally derived polymers (e.g., hyaluronic acid, chitosan), can mitigate these concerns by ensuring safe metabolization and excretion pathways. Immune responses, such as inflammation or hypersensitivity reactions, may occur due to the recognition of hydrogels or nanogels as foreign materials. Strategies such as surface functionalization with immunomodulatory agents, careful control of particle size, and the avoidance of immunogenic materials are key to mitigating these risks. Future comprehensive in vivo studies could be of major interest to better understand the long-term effects and safety pro- Pharmaceutics 2025,17, 215 37 of 47 files of these materials, thereby ensuring their suitability for clinical applications. Therefore, for these systems to succeed in the future, the creation of standardized methods is required to test them in both the preclinical and clinical stages, and regulatory agencies will need to update their guidelines to address the specific challenges posed by these advanced delivery systems, such as their dynamic properties or biodegradability. Personalized medicine and precision drug delivery: these entities can play a crucial role in this paradigm by allowing the delivery of customized therapies based on the patient’s disease profile, genetics, or even response to treatment. In the future, tailored drug release profiles may be designed considering patient needs, involving rapid release for acute conditions or controlled release for chronic diseases. Also, the incorporation of biosensors into gel systems may allow for real-time monitoring of drug release and therapeutic responses to align this information with real needs in a dynamic way. The future of hydrogels and nanogels in DDS holds tremendous potential. To realize this potential, continued advancements in material design, targeted delivery, drug release control, and scalable manufacturing will be crucial. By integrating these strategies are integrated along with regulatory challenges and personalized treatments, hydrogels and nanogels could become cornerstone technologies in the next generation of personalized, efficient, and safe drug delivery platforms. Author Contributions: Conceptualization: B.B. and A.A.; data curation: E.J.D.-P., G.M., D.C.-J. and B.B.; funding acquisition and project administration: A.A. and Y.T.; methodology: B.B., D.R.-L. and J.V.; investigation: G.M., D.C.-J. and E.J.D.-P.; writing—original draft preparation: E.J.D.-P., G.M., D.C.-J., J.L.-B., D.R.-L. and B.B.; writing—review and editing: B.B., D.C.-J., G.M., E.J.D.-P., J.L.-B., D.R.-L., J.V., A.A. and Y.T. All authors have read and agreed to the published version of the manuscript. Funding: This publication is part of the project PID2022-137911OB-I00, funded by MICIU/AEI/ 10.13039/501100011033 and by ERDF/EU. Acknowledgments: D.C., G.M. and E.J.D.-P. would like to thank Ministerio de Educación y Formación Profesional, Plan Propio de Investigación Universidad de Sevilla and Ministerio de Universidades for their respective Beca de Colaboración, University of Seville (VII_PPITUS) and FPU21/06762 grants. Authors acknowledge Plan Propio de Investigación from Universidad de Sevilla and Servicio de Biblioteca from Universidad de Sevilla as well as the Ministry of Science and Innovation for their contribution to the project through grant PDC2022-133369-I00. Conflicts of Interest: The authors declare no conflict of interest. References 1. Varma, M.V.S.; Obach, R.S.; Rotter, C.; Miller, H.R.; Chang, G.; Steyn, S.J.; El-Kattan, A.; Troutman, M.D. Physicochemical space for optimum oral bioavailability: Contribution of human intestinal absorption and first-pass elimination. J. Med. Chem. 2010,53, 1098–1108. [CrossRef] [PubMed] 2. Li, C.; Wang, J.; Wang, Y.; Gao, H.; Wei, G.; Huang, Y.; Yu, H.; Gan, Y.; Wang, Y.; Mei, L.; et al. Recent progress in drug delivery. Acta Pharm. Sin. B 2019,9, 1145–1162. [CrossRef] 3. Begines, B.; Ortiz, T.; Pérez-Aranda, M.; Martínez, G.; Merinero, M.; Argüelles-Arias, F.; Alcudia, A. Polymeric nanoparticles for drug delivery: Recent developments and future prospects. Nanomaterials 2020,10, 1403. [CrossRef] [PubMed] 4. Homayun, B.; Lin, X.; Choi, H.J. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics 2019,11, 129. [CrossRef] 5. Gopi, S.; Amalraj, A. Effective Drug Delivery System of Biopolymers Based On Nanomaterials and Hydrogels—A Review. Drug Des. Open Access 2016,5, 129. [CrossRef] 6. Wichterle, O.; Lim, D. Hydrophilic Gels for Biological Use. Nature 1960,185, 117–118. [CrossRef] 7. Dwivedi, S.; Khatri, P.; Ritu Mehra, G.; Kumar, V. Hydrogel-A Conceptual Overview. Int. J. Pharm. Biol. Arch. 2011,2, 1588–1597. Available online: www.ijpba.info (accessed on 13 September 2024). Pharmaceutics 2025,17, 215 38 of 47 8. Narayanaswamy, R.; Torchilin, V.P. Hydrogels and Their Applications in Targeted Drug Delivery. Molecules 2019,24, 603. [CrossRef] 9. Qureshi, D.; Nayak, S.K.; Maji, S.; Anis, A.; Kim, D.; Pal, K. Environment sensitive hydrogels for drug delivery applications. Eur. Polym. J. 2019,120, 109220. [CrossRef] 10. Bordbar-Khiabani, A.; Gasik, M. Smart Hydrogels for Advanced Drug Delivery Systems. Int. J. Mol. Sci. 2022,23, 3665. [CrossRef] 11. Rosiak, J.M.; Ulaiiski, P.; Rzeinicki, A. Hydrogels for biomedical purposes. Nucl. Instrum. Methods Phys. Res. B 1995,105, 335–339. [CrossRef] 12. Aswathy, S.H.; Narendrakumar, U.; Manjubala, I. Commercial hydrogels for biomedical applications. Heliyon 2020,6, e03719. [CrossRef] 13. Caló, E.; Khutoryanskiy, V.V. Biomedical applications of hydrogels: A review of patents and commercial products. Eur. Polym. J. 2015,65, 252–267. [CrossRef] 14. Ribeiro, A.M.; Magalhães, M.; Veiga, F.; Figueiras, A. Cellulose-Based Hydrogels in Topical Drug Delivery: A Challenge in Medical Devices; Springer: Berlin/Heidelberg, Germany, 2018; pp. 1–29. [CrossRef] 15. Sosnik, A.; Seremeta, K.P. Polymeric hydrogels as technology platform for drug delivery applications. Gels 2017,3, 25. [CrossRef] [PubMed] 16. Xu, J.; Strandman, S.; Zhu, J.X.X.; Barralet, J.; Cerruti, M. Genipin-crosslinked catechol-chitosan mucoadhesive hydrogels for buccal drug delivery. Biomaterials 2015,37, 395–404. [CrossRef] [PubMed] 17. Nguyen, Q.V.; Huynh, D.P.; Park, J.H.; Lee, D.S. Injectable polymeric hydrogels for the delivery of therapeutic agents: A review. Eur. Polym. J. 2015,72, 602–619. [CrossRef] 18. Cunha, S.; Forbes, B.; Lobo, J.M.S.; Silva, A.C. Improving drug delivery for alzheimer’s disease through nose-to-brain delivery using nanoemulsions, nanostructured lipid carriers (NLC) and in situ hydrogels. Int. J. Nanomed. 2021,16, 4373–4390. [CrossRef] [PubMed] 19. Hoare, T.R.; Kohane, D.S. Hydrogels in drug delivery: Progress and challenges. Polymer 2008,49, 1993–2007. [CrossRef] 20. Lee, S.C.; Kwon, I.K.; Park, K. Hydrogels for delivery of bioactive agents: A historical perspective. Adv. Drug Deliv. Rev. 2013,65, 17–20. [CrossRef] 21. Merino, S.; Martín, C.; Kostarelos, K.; Prato, M.; Vázquez, E. Nanocomposite hydrogels: 3D polymer-nanoparticle synergies for on-demand drug delivery. ACS Nano 2015,9, 4686–4697. [CrossRef] [PubMed] 22. Bhattarai, N.; Gunn, J.; Zhang, M. Chitosan-based hydrogels for controlled, localized drug delivery. Adv. Drug Deliv. Rev. 2010,62, 83–99. [CrossRef] [PubMed] 23. Ho, T.C.; Chang, C.C.; Chan, H.P.; Chung, T.W.; Shu, C.W.; Chuang, K.P.; Duh, T.H.; Yang, M.H.; Tyan, Y.C. Hydrogels: Properties and Applications in Biomedicine. Molecules 2022,27, 2902. [CrossRef] 24. Garg, S.; Garg, A. Hydrogel: Classification, Properties, Preparation and Technical Features. Asian J. Biomater. Res. 2016,2, 163–170. 25. Varaprasad, K.; Raghavendra, G.M.; Jayaramudu, T.; Yallapu, M.M.; Sadiku, R. A mini review on hydrogels classification and recent developments in miscellaneous applications. Mater. Sci. Eng. C 2017,79, 958–971. [CrossRef] [PubMed] 26. Ahmed, E.M. Hydrogel: Preparation, characterization, and applications: A review. J. Adv. Res. 2015,6, 105–121. [CrossRef] [PubMed] 27. El-Sherbiny, I.M.; Yacoub, M.H. Hydrogel scaffolds for tissue engineering: Progress and challenges. Glob. Cardiol. Sci. Pract. 2013,2013, 38. [CrossRef] 28. Gupta, P.; Vermani, K.; Garg, S. Hydrogels: From controlled release to pH-responsive drug delivery. Drug Discov. Today 2002,7, 569–579. [CrossRef] 29. Hoffman, A.S. Hydrogels for biomedical applications. Adv. Drug Deliv. Rev. 2012,64, 18–23. [CrossRef] 30. Peppas, N.A.; Langer, R. New Challenges in Biomaterials. Science 1994,263, 1715–1720. [CrossRef] [PubMed] 31. Lutolf, M.P.; Hubbell, J.A. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat. Biotechnol. 2005,23, 47–55. [CrossRef] [PubMed] 32. Mantha, S.; Pillai, S.; Khayambashi, P.; Upadhyay, A.; Zhang, Y.; Tao, O.; Pham, H.M.; Tran, S.D. Smart hydrogels in tissue engineering and regenerative medicine. Materials 2019,12, 3323. [CrossRef] 33. Annabi, N.; Tamayol, A.; Uquillas, J.A.; Akbari, M.; Bertassoni, L.E.; Cha, C.; Camci-Unal, G.; Dokmeci, M.R.; Peppas, N.A.; Khademhosseini, A. 25th anniversary article: Rational design and applications of hydrogels in regenerative medicine. Adv. Mater. 2014,26, 85–124. [CrossRef] [PubMed] 34. Skoulas, D.; Mangiapia, G.; Parisi, D.; Kasimatis, M.; Glynos, E.; Stratikos, E.; Vlassopoulos, D.; Frielinghaus, H.; Iatrou, H. Tunable Hydrogels with Improved Viscoelastic Properties from Hybrid Polypeptides. Macromolecules 2021,54, 10786–10800. [CrossRef] 35. Cui, L.; Yao, Y.; Yim, E.K.F. The effects of surface topography modification on hydrogel properties. APL Bioeng. 2021,5, 031509. [CrossRef] [PubMed] 36. Hense, D.; Strube, O.I. Glutaraldehyde Cross-Linking of Salt-Induced Fibrinogen Hydrogels. ACS Biomater. Sci. Eng. 2024,10, 6927–6937. [CrossRef] 37. Yang, X.; Mohseni, M.; Bas, O.; Meinert, C.; New, E.J.; Castro, N.J. Type II Photoinitiator and Tuneable Poly(Ethylene Glycol)-Based Materials Library for Visible Light Photolithography. Tissue Eng. Part A 2020,26, 292–304. [CrossRef] [PubMed] Pharmaceutics 2025,17, 215 39 of 47 38. Sapuła, P.; Bialik-W˛as, K.; Malarz, K. Are Natural Compounds a Promising Alternative to Synthetic Cross-Linking Agents in the Preparation of Hydrogels? Pharmaceutics 2023,15, 253. [CrossRef] 39. Mohamed, A.L.; Soliman, A.A.F.; Ali, E.A.; Abou-Zeid, N.Y.; Nada, A.A. Hydrogel bioink based on clickable cellulose derivatives: Synthesis, characterization and in vitro assessment. Int. J. Biol. Macromol. 2020,163, 888–897. [CrossRef] [PubMed] 40. Mauri, E.; Giannitelli, S.M.; Trombetta, M.; Rainer, A. Synthesis of Nanogels: Current Trends and Future Outlook. Gels 2021,7, 36. [CrossRef] 41. Ahmed, S.; Alhareth, K.; Mignet, N. Advancement in nanogel formulations provides controlled drug release. Int. J. Pharm. 2020,584, 119435. [CrossRef] [PubMed] 42. Webber, M.J.; Pashuck, E.T. (Macro)molecular self-assembly for hydrogel drug delivery. Adv. Drug Deliv. Rev. 2021,172, 275–295. [CrossRef] [PubMed] 43. Ravarino, P.; Giuri, D.; Faccio, D.; Tomasini, C. Designing a transparent and fluorine containing hydrogel. Gels 2021,7, 43. [CrossRef] [PubMed] 44. Romero, J.F.; Diaz-Barrios, A.; Gonzalez, G. Biocompatible thermo-responsive N-vinylcaprolactam based hydrogels for controlled drug delivery systems. Bionatura 2021,6, 1712–1719. [CrossRef] 45. Wang, Y.; Li, Q.; Zhou, J.-E.; Tan, J.; Li, M.; Xu, N.; Qu, F.; Chen, J.; Li, J.; Wang, J.; et al. A Photopolymerized Semi-Interpenetrating Polymer Networks-Based Hydrogel Incorporated with Nanoparticle for Local Chemotherapy of Tumors. Pharm. Res. 2021,38, 669–680. [CrossRef] [PubMed] 46. Chen, H.; Zhang, X.; Lin, Z.; Zhang, R.; Yu, B.; Li, Y.; Xu, F.-J. In Situ Preparation of Mechanically Enhanced Hydrogel via Dispersion Polymerization in Aqueous Solution. Macromol. Rapid Commun. 2021,42, 2100028. [CrossRef] [PubMed] 47. Wang, Z.; Wu, J.; Shi, X.; Song, F.; Gao, W.; Liu, S. Stereocomplexation of Poly(lactic acid) and Chemical Crosslinking of Ethylene Glycol Dimethacrylate (EGDMA) Double-Crosslinked Temperature/pH Dual Responsive Hydrogels. Polymers 2020,12, 2204. [CrossRef] [PubMed] 48. Debertrand, L.; Zhao, J.; Creton, C.; Narita, T. Swelling and Mechanical Properties of Polyacrylamide-Derivative Dual-Crosslink Hydrogels Having Metal–Ligand Coordination Bonds as Transient Crosslinks. Gels 2021,7, 72. [CrossRef] [PubMed] 49. Ferozekhan, S.; Umashankar, M.S.; Narayanasamy, D. A Comprehensive Review of Nanogel-Based Drug Delivery Systems. Cureus 2024,16, e68633. [CrossRef] 50. Li, Z.; Van Zee, N.J.; Bates, F.S.; Lodge, T.P. Polymer Nanogels as Reservoirs to Inhibit Hydrophobic Drug Crystallization. ACS Nano 2019,13, 1232–1243. [CrossRef] 51. Abdel-Rashid, R.S.; Helal, D.A.; Omar, M.M.; El Sisi, A.M. Nanogel loaded with surfactant based nanovesicles for enhanced ocular delivery of acetazolamide. Int. J. Nanomed. 2019,14, 2973–2983. [CrossRef] 52. Bewersdorff, T.; Gruber, A.; Eravci, M.; Dumbani, M.; Klinger, D.; Haase, A. Amphiphilic nanogels: Influence of surface hydrophobicity on protein corona, biocompatibility and cellular uptake. Int. J. Nanomed. 2019,14, 7861–7878. [CrossRef] 53. Tang, W.; Han, L.; Duan, S.; Lu, X.; Wang, Y.; Wu, X.; Liu, J.; Ding, B. An Aptamer-Modified DNA Tetrahedron-Based Nanogel for Combined Chemo/Gene Therapy of Multidrug-Resistant Tumors. ACS Appl. Bio Mater. 2021,4, 7701–7707. [CrossRef] [PubMed] 54. Carniato, F.; Ricci, M.; Tei, L.; Garello, F.; Furlan, C.; Terreno, E.; Ravera, E.; Parigi, G.; Luchinat, C.; Botta, M. Novel Nanogels Loaded with Mn(II) Chelates as Effective and Biologically Stable MRI Probes. Small 2023,19, e2302868. [CrossRef] [PubMed] 55. Sharpe, L.A.; Daily, A.M.; Horava, S.D.; Peppas, N.A. Therapeutic applications of hydrogels in oral drug delivery. Expert Opin. Drug Deliv. 2014,11, 901–915. [CrossRef] 56. Edwards, J. Hydrogels and their potential uses in burn wound management. Br. J. Nurs. 2010,19, S12–S16. [CrossRef] [PubMed] 57. Chen, T.; Chen, Y.; Rehman, H.U.; Chen, Z.; Yang, Z.; Wang, M.; Li, H.; Liu, H. Ultratough, Self-Healing, and Tissue-Adhesive Hydrogel for Wound Dressing. ACS Appl. Mater. Interfaces 2018,10, 33523–33531. [CrossRef] 58. Basu, A.; Lindh, J.; Ålander, E.; Strømme, M.; Ferraz, N. On the use of ion-crosslinked nanocellulose hydrogels for wound healing solutions: Physicochemical properties and application-oriented biocompatibility studies. Carbohydr. Polym. 2017,174, 299–308. [CrossRef] [PubMed] 59. Hu, H.; Xu, F.J. Rational design and latest advances of polysaccharide-based hydrogels for wound healing. Biomater. Sci. 2020,8, 2084–2101. [CrossRef] 60. Li, J.; Yu, F.; Chen, G.; Liu, J.; Li, X.L.; Cheng, B.; Mo, X.M.; Chen, C.; Pan, J.F. Moist-Retaining, Self-Recoverable, Bioadhesive, and Transparent in Situ Forming Hydrogels to Accelerate Wound Healing. ACS Appl. Mater. Interfaces 2020,12, 2023–2038. [CrossRef] [PubMed] 61. Liu, W.; Ou-Yang, W.; Zhang, C.; Wang, Q.; Pan, X.; Huang, P.; Zhang, C.; Li, Y.; Kong, D.; Wang, W. Synthetic polymeric antibacterial hydrogel for methicillin-resistant staphylococcus aureus-infected wound healing: Nanoantimicrobial self-assembly, drugAnd cytokine-free strategy. ACS Nano 2020,14, 12905–12917. [CrossRef] 62. Cheng, S.; Wang, H.; Pan, X.; Zhang, C.; Zhang, K.; Chen, Z.; Dong, W.; Xie, A.; Qi, X. Dendritic Hydrogels with Robust Inherent Antibacterial Properties for Promoting Bacteria-Infected Wound Healing. ACS Appl. Mater. Interfaces 2022,14, 11144–11155. [CrossRef] Pharmaceutics 2025,17, 215 40 of 47 63. Chen, H.; Xing, X.; Tan, H.; Jia, Y.; Zhou, T.; Chen, Y.; Ling, Z.; Hu, X. Covalently antibacterial alginate-chitosan hydrogel dressing integrated gelatin microspheres containing tetracycline hydrochloride for wound healing. Mater. Sci. Eng. C 2017,70, 287–295. [CrossRef] [PubMed] 64. Manna, S.; Ghosh, A.K.; Mandal, S.M. Curd-peptide based novel hydrogel inhibits biofilm formation, quorum sensing, swimming mortility of multi-antibiotic resistant clinical isolates and accelerates wound healing activity. Front. Microbiol. 2019,10, 951. [CrossRef] [PubMed] 65. Fan, Z.; Liu, B.; Wang, J.; Zhang, S.; Lin, Q.; Gong, P.; Ma, L.; Yang, S. A novel wound dressing based on Ag/graphene polymer hydrogel: Effectively kill bacteria and accelerate wound healing. Adv. Funct. Mater. 2014,24, 3933–3943. [CrossRef] 66. Song, S.; Liu, Z.; Abubaker, M.A.; Ding, L.; Zhang, J.; Yang, S.; Fan, Z. Antibacterial polyvinyl alcohol/bacterial cellulose/nanosilver hydrogels that effectively promote wound healing. Mater. Sci. Eng. C 2021,126, 112171. [CrossRef] [PubMed] 67. Zhang, M.; Qiao, X.; Han, W.; Jiang, T.; Liu, F.; Zhao, X. Alginate-chitosan oligosaccharide-ZnO composite hydrogel for accelerating wound healing. Carbohydr. Polym. 2021,266, 118100. [CrossRef] 68. Kong, X.; Fu, J.; Shao, K.; Wang, L.; Lan, X.; Shi, J. Biomimetic hydrogel for rapid and scar-free healing of skin wounds inspired by the healing process of oral mucosa. Acta Biomater. 2019,100, 255–269. [CrossRef] [PubMed] 69. Thangavel, P.; Ramachandran, B.; Kannan, R.; Muthuvijayan, V. Biomimetic hydrogel loaded with silk and l-proline for tissue engineering and wound healing applications. J. Biomed. Mater. Res.-Part B Appl. Biomater. 2017,105, 1401–1408. [CrossRef] 70. Wei, Q.; Ma, L.; Zhang, W.; Ma, G.; Hu, Z. EGCG-crosslinked carboxymethyl chitosan-based hydrogels with inherent desired functions for full-thickness skin wound healing. J. Mater. Chem. B 2022,10, 3927–3935. [CrossRef] 71. Gao, Y.; Li, Z.; Huang, J.; Zhao, M.; Wu, J. In situ formation of injectable hydrogels for chronic wound healing. J. Mater. Chem. B 2020,8, 8768–8780. [CrossRef] 72. Du, X.; Liu, Y.; Wang, X.; Yan, H.; Wang, L.; Qu, L.; Kong, D.; Qiao, M.; Wang, L. Injectable hydrogel composed of hydrophobically modified chitosan/oxidized-dextran for wound healing. Mater. Sci. Eng. C 2019,104, 109930. [CrossRef] [PubMed] 73. Balitaan, J.N.I.; Luo, W.-J.; Su, Y.-W.; Yu, C.-Y.; Wu, T.-Y.; Chang, C.-A.; Jia, H.-W.; Lin, S.-R.; Hsiao, C.-D.; Yeh, J.-M. Healing Wounds Efficiently with Biomimetic Soft Matter: Injectable Self-Healing Neutral Glycol Chitosan/Dibenzaldehyde-Terminated Poly(ethylene glycol) Hydrogel with Inherent Antibacterial Properties. ACS Appl. Bio Mater. 2023,6, 552–565. [CrossRef] [PubMed] 74. Cai, D.; Yang, Y.; Lu, J.; Yuan, Z.; Zhang, Y.; Yang, X.; Huang, X.; Li, T.; Tian, X.; Xu, B.; et al. Injectable Carrier-Free Hydrogel Dressing with Anti-Multidrug-Resistant Staphylococcus aureus and Anti-Inflammatory Capabilities for Accelerated Wound Healing. ACS Appl. Mater. Interfaces 2022,14, 43035–43049. [CrossRef] [PubMed] 75. Chen, H.; Cheng, R.; Zhao, X.; Zhang, Y.; Tam, A.; Yan, Y.; Shen, H.; Zhang, Y.S.; Qi, J.; Feng, Y.; et al. An injectable self-healing coordinative hydrogel with antibacterial and angiogenic properties for diabetic skin wound repair. NPG Asia Mater. 2019,11, 3. [CrossRef] 76. Zhang, W.; Qi, X.; Zhao, Y.; Liu, Y.; Xu, L.; Song, X.; Xiao, C.; Yuan, X.; Zhang, J.; Hou, M. Study of injectable Blueberry anthocyanins-loaded hydrogel for promoting full-thickness wound healing. Int. J. Pharm. 2020,586, 119543. [CrossRef] [PubMed] 77. Wang, J.; Wang, Y.; Sun, X.; Liu, D.; Huang, C.; Wu, J.; Yang, C.; Zhang, Q. Biomimetic cartilage scaffold with orientated porous structure of two factors for cartilage repair of knee osteoarthritis. Artif. Cells Nanomed. Biotechnol. 2019,47, 1710–1721. [CrossRef] [PubMed] 78. Radhakrishnan, J.; Manigandan, A.; Chinnaswamy, P.; Subramanian, A.; Sethuraman, S. Gradient nano-engineered in situ forming composite hydrogel for osteochondral regeneration. Biomaterials 2018,162, 82–98. [CrossRef] 79. Lin, N.; Gèze, A.; Wouessidjewe, D.; Huang, J.; Dufresne, A. Biocompatible Double-Membrane Hydrogels from Cationic Cellulose Nanocrystals and Anionic Alginate as Complexing Drugs Codelivery. ACS Appl. Mater. Interfaces 2016,8, 6880–6889. [CrossRef] 80. Gao, F.; Xu, Z.; Liang, Q.; Li, H.; Peng, L.; Wu, M.; Zhao, X.; Cui, X.; Ruan, C.; Liu, W. Osteochondral Regeneration with 3D-Printed Biodegradable High-Strength Supramolecular Polymer Reinforced-Gelatin Hydrogel Scaffolds. Adv. Sci. 2019,6, 1900867. [CrossRef] [PubMed] 81. Yang, H.; Ji, M.; Yang, M.; Shi, M.; Pan, Y.; Zhou, Y.; Qi, H.J.; Suo, Z.; Tang, J. Fabricating hydrogels to mimic biological tissues of complex shapes and high fatigue resistance. Matter 2021,4, 1935–1946. [CrossRef] 82. Gungor-Ozkerim, P.S.; Inci, I.; Zhang, Y.S.; Khademhosseini, A.; Dokmeci, M.R. Bioinks for 3D bioprinting: An overview. Biomater. Sci. 2018,6, 915–946. [CrossRef] 83. Nadernezhad, A.; Caliskan, O.S.; Topuz, F.; Afghah, F.; Erman, B.; Koc, B. Nanocomposite Bioinks Based on Agarose and 2D Nanosilicates with Tunable Flow Properties and Bioactivity for 3D Bioprinting. ACS Appl. Bio Mater. 2019,2, 796–806. [CrossRef] 84. Kolesky, D.B.; Homan, K.A.; Skylar-Scott, M.A.; Lewis, J.A. Three-dimensional bioprinting of thick vascularized tissues. Proc. Natl. Acad. Sci. USA 2016,113, 3179–3184. [CrossRef] 85. Zhang, Y.; Wu, B.M. Current Advances in Stimuli-Responsive Hydrogels as Smart Drug Delivery Carriers. Gels 2023,9, 838. [CrossRef] [PubMed] 86. Valentino, A.; Yazdanpanah, S.; Conte, R.; Calarco, A.; Peluso, G. Smart Nanocomposite Hydrogels as Next-Generation Therapeutic and Diagnostic Solutions. Gels 2024,10, 689. [CrossRef] [PubMed] Pharmaceutics 2025,17, 215 41 of 47 87. Liu, J.; Du, C.; Huang, W.; Lei, Y. Injectable smart stimuli-responsive hydrogels: Pioneering advancements in biomedical applications. Biomater. Sci. 2023,12, 8–56. [CrossRef] 88. Olteanu, G.; Neac s , u, S.M.; Joi t , a, F.A.; Musuc, A.M.; Lupu, E.C.; Ioni t , ă-Mîndrican, C.-B.; Lupuliasa, D.; Mititelu, M. Advancements in Regenerative Hydrogels in Skin Wound Treatment: A Comprehensive Review. Int. J. Mol. Sci. 2024,25, 3849. [CrossRef] [PubMed] 89. Ninan, N.; Forget, A.; Shastri, V.P.; Voelcker, N.H.; Blencowe, A. Antibacterial and Anti-Inflammatory pH-Responsive Tannic Acid-Carboxylated Agarose Composite Hydrogels for Wound Healing. ACS Appl. Mater. Interfaces 2016,8, 28511–28521. [CrossRef] [PubMed] 90. Ma, M.; Zhong, Y.; Jiang, X. Thermosensitive and pH-responsive tannin-containing hydroxypropyl chitin hydrogel with longlasting antibacterial activity for wound healing. Carbohydr. Polym. 2020,236, 116096. [CrossRef] 91. Yan, M.; Chen, T.; Zhang, S.; Lu, T.; Sun, X. A core-shell structured alginate hydrogel beads with tunable thickness of carboxymethyl cellulose coating for pH responsive drug delivery. J. Biomater. Sci. Polym. Ed. 2021,32, 763–778. [CrossRef] 92. Zhu, J.; Cai, H.; Xu, C.; Wang, W.; Song, X.; Li, B.; Shen, Y.; Dong, X. Acidity-Responsive Nanoreactors Destructed “Warburg Effect” for Toxic-Acidosis and Starvation Synergistic Therapy. Small 2023,19, 2304058. [CrossRef] [PubMed] 93. Icard, P.; Shulman, S.; Farhat, D.; Steyaert, J.-M.; Alifano, M.; Lincet, H. How the Warburg effect supports aggressiveness and drug resistance of cancer cells? Drug Resist. Updates 2018,38, 1–11. [CrossRef] [PubMed] 94. Sonawane, S.J.; Kalhapure, R.S.; Govender, T. Hydrazone linkages in pH responsive drug delivery systems. Eur. J. Pharm. Sci. 2017,99, 45–65. [CrossRef] [PubMed] 95. Liao, J.; Peng, H.; Liu, C.; Li, D.; Yin, Y.; Lu, B.; Zheng, H.; Wang, Q. Dual pH-responsive-charge-reversal micelle platform for enhanced anticancer therapy. Mater. Sci. Eng. C 2021,118, 111527. [CrossRef] 96. Wu, M.; Chen, J.; Huang, W.; Yan, B.; Peng, Q.; Liu, J.; Chen, L.; Zeng, H. Injectable and Self-Healing Nanocomposite Hydrogels with Ultrasensitive pH-Responsiveness and Tunable Mechanical Properties: Implications for Controlled Drug Delivery. Biomacromolecules 2020,21, 2409–2420. [CrossRef] 97. Qu, J.; Zhao, X.; Ma, P.X.; Guo, B. pH-responsive self-healing injectable hydrogel based on N-carboxyethyl chitosan for hepatocellular carcinoma therapy. Acta Biomater. 2017,58, 168–180. [CrossRef] 98. Solomevich, S.O.; Bychkovsky, P.M.; Yurkshtovich, T.L.; Golub, N.V.; Mirchuk, P.Y.; Revtovich, M.Y.; Shmak, A.I. Biodegradable pH-sensitive prospidine-loaded dextran phosphate based hydrogels for local tumor therapy. Carbohydr. Polym. 2019,226, 115308. [CrossRef] [PubMed] 99. Raza, F.; Zhu, Y.; Chen, L.; You, X.; Zhang, J.; Khan, A.; Khan, M.W.; Hasnat, M.; Zafar, H.; Wu, J.; et al. Paclitaxel-loaded pH responsive hydrogel based on self-assembled peptides for tumor targeting. Biomater. Sci. 2019,7, 2023–2036. [CrossRef] [PubMed] 100. Liu, Y.; Ran, Y.; Ge, Y.; Raza, F.; Li, S.; Zafar, H.; Wu, Y.; Paiva-Santos, A.C.; Yu, C.; Sun, M.; et al. pH-Sensitive Peptide Hydrogels as a Combination Drug Delivery System for Cancer Treatment. Pharmaceutics 2022,14, 652. [CrossRef] 101. Dong, A.; Huang, S.; Qian, Z.; Xu, S.; Yuan, W.; Wang, B. A pH-responsive supramolecular hydrogel encapsulating a CuMnS nanoenzyme catalyst for synergistic photothermal–photodynamic–chemodynamic therapy of tumours. J. Mater. Chem. B 2023,11, 10883–10895. [CrossRef] [PubMed] 102. Khan, R.; Zaman, M.; Salawi, A.; Khan, M.A.; Iqbal, M.O.; Riaz, R.; Ahmed, M.M.; Butt, M.H.; Alvi, M.N.; Almoshari, Y.; et al. Synthesis of Chemically Cross-Linked pH-Sensitive Hydrogels for the Sustained Delivery of Ezetimibe. Gels 2022,8, 281. [CrossRef] [PubMed] 103. Lin, X.; Miao, L.; Wang, X.; Tian, H. Design and evaluation of pH-responsive hydrogel for oral delivery of amifostine and study on its radioprotective effects. Colloids Surf. B Biointerfaces 2020,195, 111200. [CrossRef] 104. Bai, X.; Bao, Z.; Bi, S.; Li, Y.; Yu, X.; Hu, S.; Tian, M.; Zhang, X.; Cheng, X.; Chen, X. Chitosan-Based Thermo/pH Double Sensitive Hydrogel for Controlled Drug Delivery. Macromol. Biosci. 2018,18, 1700305. [CrossRef] [PubMed] 105. Huang, Y.; Wang, Z.; Zhang, G.; Ren, J.; Yu, L.; Liu, X.; Yang, Y.; Ravindran, A.; Wong, C.; Chen, R. A pH/redox-dual responsive, nanoemulsion-embedded hydrogel for efficient oral delivery and controlled intestinal release of magnesium ions. J. Mater. Chem. B 2021,9, 1888–1895. [CrossRef] [PubMed] 106. Gou, M.; Li, X.; Dai, M.; Gong, C.; Wang, X.; Xie, Y.; Deng, H.; Chen, L.; Zhao, X.; Qian, Z.; et al. A novel injectable local hydrophobic drug delivery system: Biodegradable nanoparticles in thermo-sensitive hydrogel. Int. J. Pharm. 2008,359, 228–233. [CrossRef] 107. Sim, H.J.; Thambi, T.; Lee, D.S. Heparin-based temperature-sensitive injectable hydrogels for protein delivery. J. Mater. Chem. B 2015,3, 8892–8901. [CrossRef] [PubMed] 108. Liang, H.-F.; Hong, M.-H.; Ho, R.-M.; Chung, C.-K.; Lin, Y.-H.; Chen, C.-H.; Sung, H.-W. Novel Method Using a TemperatureSensitive Polymer (Methylcellulose) to Thermally Gel Aqueous Alginate as a pH-Sensitive Hydrogel. Biomacromolecules 2004,5, 1917–1925. [CrossRef]