Sweet MOFs: exploring the potential and restraints of integrating carbohydrates with metal-organic frameworks for biomedical applications

258 | Nanoscale Horiz., 2025, 10, 258–278 This journal is © The Royal Society of Chemistry 2025 Cite this: Nanoscale Horiz., 2025, 10, 258 ‘‘Sweet MOFs’’: exploring the potential and restraints of integrating carbohydrates with metal–organic frameworks for biomedical applications Alessio Zuliani, a Victor Ramos, a Alberto Escudero ab and Noureddine Khiar * a The unique features of metal–organic frameworks (MOFs) such as biodegradability, reduced toxicity and high surface area offer the possibility of developing smart nanosystems for biomedical applications through the simultaneous functionalization of their structure with biologically relevant ligands and the loading of biologically active cargos, ranging from small drugs to large biomacromolecules, into their pores. Aiming to develop efficient, naturally inspired biocompatible systems, recent research has combined organic and materials chemistry to design innovative composites that exploit carbohydrate chemistry for the functionalization and structural modification of MOFs. Scientific investigation in the field has seen a significant rise in the past five years, and it is becoming crucial to acknowledge both the limits and benefits of this approach for future investigation. In this review, the latest research results merging carbohydrates and MOFs are discussed, with a particular emphasis on the advances in the field and the remaining challenges, including addressing sustainability and real-case applicability. Introduction Carbohydrates (CHs), fundamental building blocks of life alongside lipids, proteins, and nucleic acids, have long captivated researchers with their diverse structure and biological functionalities. Beyond their crucial role in biological signalling, CHs exhibit a myriad of other biological functions, including energy storage, organelle protection, modulation of peptide or protein properties, mediating cellular and extracellular interactions, but also immune response, inflammation and tumor cell metastasis. 1 Besides, different CHs mediate interactions with pathogens during the early and crucial stages of infection, as happens with the adherent-invasive and uropathogenic (UPEC) Escherichia coli, HIV-1 virus, influenza, Ebola and coronavirus. 2 For example, it has been demonstrated that the entry of SARS-CoV2 pseudo-typed virus into cells can significantly be inhibited by heparin. 3 CHs are also involved in bacterial infection processes. This is the case for Pseudomonas aeruginosa, a bacterium that is a leading cause of morbidity and mortality in cystic fibrosis patients and immunocompromised individuals, which specifically targets galactose and strongly binds to fucose and fucose-containing oligosaccharides to adhere to epithelial cells. These essential biological interactions, combined with their biocompatibility and biodegradability, make CHs ideal for a wide range of biomedical applications, spanning from glycobased drugs, 4,5 drug delivery, diagnosis, and imaging to tissue engineering, wound healing, and antiviral/antimicrobial treatments. 6–10 Nevertheless, the direct use of CHs in biomedical applications is often limited by their structural complexity, low affinity, poor stability, rapid degradation in the body, and lack of controlled release of eventually coupled drugs. Additionally, their solubility and targeting abilities can be suboptimal without further modification. As a result, during the last two decades, research has focused on the design of a variety of glyconanomaterials capable of addressing these intrinsic limitations of CHs, including hydrogels, nanotubes, liposomes, micelles, nanoparticles, dendrimers, and metal–organic frameworks (MOFs). 11–20 These CH-based nanosystems feature unique characteristics, such as high avidity coupled with specific recognition by various cell surface receptors, which significantly enhance the receptor-mediated uptake of nanocarriers, thanks also to the exploitation of multivalency, i.e., the presence of multiple copies of the same element on the surface of each nanovector. 21 For example, surface modifications employing specific sugars, such as D-mannose, have been demonstrated to increase the receptora Asymmetric Synthesis and Nanosystems Group (Art&Fun), Institute for Chemical Research (IIQ), CSIC-University of Seville, 41092 Seville, Spain. E-mail: [email protected] b Inorganic Chemistry Department, University of Seville, Calle Profesor Garcı ´a Gonza ´lez 1, 41012 Seville, Spain Received 15th October 2024, Accepted 1st November 2024 DOI: 10.1039/d4nh00525b rsc.li/nanoscale-horizons Nanoscale Horizons REVIEW Open Access Article. Published on 04 November 2024. Downloaded on 5/15/2025 8:42:36 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online View Journal | View Issue This journal is © The Royal Society of Chemistry 2025 Nanoscale Horiz., 2025, 10, 258–278 | 259 mediated uptake of nanocarriers of drugs, 22 whereas modifications with other saccharides, like dextrin (a glucose polysaccharide), can mitigate nonspecific cellular uptake. 23 Moreover, CH-based nanocarriers which are partially or entirely composed of saccharides, are susceptible to cellular degradation, leading to the subsequent release of the payload. This property is particularly beneficial for the clearance of these materials from the body and for triggering drug release or activation by specific enzymes. CHs can also be encapsulated inside specific nanostructures, in order to guarantee protection of the drug from enzymatic degradation, controlled release kinetics, targeted delivery to affected areas, and enhanced bioavailability. 24 Among all, the combination of CHs with metal–organic frameworks (MOFs) has garnered significant interest based on the exploitation of their unique features including their ability to load different active molecules thanks to their adjustable porosity and pore sizes, and their variable composition that allows the incorporation of a variety of multivariate structures with single, double, or triple metal systems and/or organic linkers. Additionally, they can utilize flexible linkers and versatile inorganic building units in terms of geometry. Furthermore, MOFs can undergo post-synthetic modifications (PSM) to introduce new functional groups, which can be applied to both the external surfaces and internal pore structures. 25–27 Even though the first articles related to MOFs and CH-based nanosystems can be dated back to the early 2010s, 28,29 the flowering of this research area only began not long ago, starting around 2020. This recent blossoming initiated thanks to the improvements in the technologies and methodologies for the preparation of MOFs and in carbohydrate synthetic processes, as well as to the breakthroughs in immunotherapy, targeted treatments, nanomedicine, and personalized medicine. 30–32 Thus, this field of research is still in its infancy, although it is rapidly growing. The nanostructures forged by the fusion of CHs and MOFs, which we have poetically defined as ‘‘Sweet’’ MOFs and referred from here on as ‘‘CHs-MOFs’’ for convenience and ease of reading, present a compelling opportunity in the field of biomedicine, as these systems merge the advantageous properties of both components. From a theoretical perspective, CHsMOFs offer several unique features that distinguish them from other nanoparticles for biomedical applications including: Enhanced biocompatibility: CHs, as natural occurring chemicals, can improve the compatibility of MOFs within biological environments, reducing potential toxicity concerns commonly associated with synthetic materials. This biocompatibility is critical for applications such as drug delivery or tissue engineering, where the interaction of the material with the body must be benign and support cellular functions. Furthermore, the introduction of CHs with finely designed molecular structure can allow for the targeting of specific receptors. For example, sialic acids, particularly N-acetylneuraminic acid (Neu5Ac), target Siglec receptors on immune cells to modulate immune responses, with applications in immune regulation and cancer immunotherapy. 33 Also, heparan sulfate, a highly sulfated glycosaminoglycan, has been studied for the potential targeting of heparan sulfate proteoglycan (HSPG) receptors on cells, with applications in inhibiting viral entry and targeting angiogenesis in cancer therapy. 34 Porous structure: MOFs possess highly tuneable, porous frameworks that are ideal for encapsulating therapeutic agents. The porous nature protects the drug molecules from premature degradation and facilitates controlled release, which is essential for achieving sustained therapeutic effects. CHs can further assist in modulating this release profile, leveraging their responsiveness to biological cues such as enzymatic degradation or pH changes. 35,36 Modular nature: the combination of CHs and MOFs enables the design of nanosystems with customizable physicochemical properties, including size, surface charge, and hydrophobicity. This tunability enhances the targeting specificity and therapeutic efficacy of drug delivery systems, offering opportunities for personalized medicine and treatments that demand high precision, such as in cancer or gene therapy. 37,38 Nevertheless, despite the potential of CHs-MOFs, several substantial challenges remain: (I) scalability and reproducibility remain major concerns, as the synthesis of MOFs often relies on intricate protocols that may hinder large-scale production; (II) the sustainable features of these nanosystems are also a poorly explored theme, in contrast with recent trends and modern environmental policies; (III) ensuring the long-term stability of CHs-MOFs in complex biological environments poses a formidable obstacle, requiring meticulous optimization and characterization; (IV) elucidating and optimizing the intricate interplay between CHs and MOFs within biological systems is imperative to address their full therapeutic potential. The current literature reports several relevant reviews on the exploitation of MOFs in biomedicine, spanning applications from drug delivery systems (DDSs) for cancer therapy and diagnostics (theragnostic) for antibacterial and wound healing systems. 39–42 For example, some studies focus on single and multiple stimuli-responsive DDSs, while others explore polymer/MOF hybrid systems and MOF-based DDSs for advanced drug delivery, emphasizing drug loading strategies, applications, biopharmaceutics, and quality control. 37,38,42–44 To the best of our knowledge, the only reviews relating to CHs and MOFs were specifically focused on cyclodextrin-based MOFs (CD-MOFs), including a review reported by Stoddart et al., 45 another one by Huang et al., who focused on biological MOFs made with different bioligands, including cyclodextrins, 46 and a recent review by Cha and collaborators. 47 A book chapter exploring the field of CD-MOFs is also available in the literature. 26 A review from 2020 explored the theme of CHMOFs as part of the different bio entities coupled with MOFs. 35 In contrast, this review aims at providing a general overview of the different classes of materials derived from the combination of CHs and MOFs, contributing to a concise summary of the current state-of-the-art research toward future developments. More in detail, this review delves into the exclusive characteristics and current limitations of the strategies for merging CH chemistry with MOFs for biomedical purposes, with a brief look at industrial interests and prospects. The title, ‘‘Sweet MOFs’’, is a tribute to the etymology and ancient Review Nanoscale Horizons Open Access Article. Published on 04 November 2024. Downloaded on 5/15/2025 8:42:36 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online 260 | Nanoscale Horiz., 2025, 10, 258–278 This journal is © The Royal Society of Chemistry 2025 meaning of the term ‘‘saccharide’’, from the Latin ‘‘saccharum’’, defined as ‘‘...a kind of honey found in cane, white as gum, and it crunches between the teeth...’’ (Pliny the Elder), derived from the Ancient Greek word sa 0kwaron(sakkharon). 48 The review firstly reports a brief discussion of the most studied CHs and MOFs for the preparation of CHs-MOFs. In particular, the biological role and uses of the CHs are summarised as well as the characteristics of the main classes of MOFs studied for biomedical applications. Then, the review is subdivided into two sections, one focused on the most recent strategies for the post synthetic modification (PSM) of MOFs with CHs, forming the so-defined CHs-on-MOFs, 35 and the other focusing on the incorporation of carbohydrates during the synthesis of MOFs, whether as part of the same structure as the MOF or encapsulated in it, i.e., CHs@MOFs, 35 as summarised in Fig. 1. Finally, this review reports some selected examples of preclinical trials of CHs-MOFs, followed by an outlook and conclusion section. Most studied carbohydrates and MOFs for the development of CHs-MOFs Carbohydrates Serving as a primary source of energy for living organisms and covering other biological functions ranging from cell signalling and cellular recognition to structural support to cells, CHs, herein referred as a synonym of saccharide, 49 encompass different classes of compounds, i.e., simple monosaccharides, such as glucose and fructose, disaccharides, such as sucrose and lactose, oligosaccharides, containing a small number of sugar units (usually 3–10), and polysaccharides, such as starch, glycogen, and cellulose. CHs are incorporated into CHs-MOFs to enhance various functional properties, including: Improved biocompatibility: for example, when CHs are used as building units in CHs-MOFs, their degradation products are non-toxic, minimizing concerns related to toxicity. Enhanced solubility and dispersibility: the hydrophilic nature of CHs boosts the aqueous solubility and colloidal stability of MOFs, improving their behaviour in biological systems. Enhanced avidity: to offset the intrinsically low affinity associated with monomeric carbohydrate–protein binding interactions. 50 Targeting capabilities: specific CHs can be designed to interact with cellular receptors, enabling targeted delivery of drugs or imaging agents to specific tissues or cell types. Controlled release of active compounds: CHs-MOFs can be engineered to regulate the release kinetics of encapsulated drugs or other active agents, ensuring sustained or stimuliresponsive delivery. For example, CHs can also function as ‘‘gatekeepers’’ by forming a film around drug-loaded MOFs, Fig. 1 Scheme of the most common strategies for the preparation of carbohydrate-MOFs (CHs-MOFs). Fig. 2 Structures of the most studied carbohydrates for the preparation of CHs-MOFs. Nanoscale Horizons Review Open Access Article. Published on 04 November 2024. Downloaded on 5/15/2025 8:42:36 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry 2025 Nanoscale Horiz., 2025, 10, 258–278 | 261 controlling the release of the drugs as the film gradually degrades. 51 Currently, the main CHs utilized for designing CHs-MOFs for biomedical applications encompass a wide array of compounds and their derivatives, such as chitosan, hyaluronic acid, dextran, cylodextrins, glucose and galactose. Chitosan, derived from chitin, stands out for its biocompatibility and adhesive properties, finding utility in drug delivery, gene therapy, imaging, and tissue engineering. 52 Meanwhile, the compatibility and ability to target specific cancer cell receptors of hyaluronic acid (HA) make it valuable for targeted drug delivery and cancer imaging. 53 Dextrancoated MOFs offer versatility in drug delivery, imaging, and theragnostic applications, thanks to their biocompatibility and stealth properties. 54 Cyclodextrin-functionalized MOFs excel at encapsulating hydrophobic drugs, enhancing their solubility and stability. 55 Glucose-functionalized MOFs are engineered to precisely target cancer cells while minimizing off-target effects by leveraging glucose transporter overexpression. 56 Similarly, galactose-MOFs exhibit targeting capabilities for liver cells, promising advancements in liver-targeted drug delivery and imaging. 57 Fig.2summarisesthemainindustrialusesaswell as the principal large-scale production methods among the most studied CHs – and their derivatives–forthepreparationofCHsMOFs, including glucose, cyclodextrins (CD), chitosan, galactose, mannose, and glycosaminoglycans (GAGs). MOFs Metal organic frameworks (MOFs), unique structures of metalcontaining inorganic building units, i.e., metal ions or metal clusters, connected to multidentate organic building units, i.e., (organic) linkers, via coordination bonding, belong to the almost 30-year old class of reticular materials. MOFs exhibit highly adjustable physicochemical and structural properties, which in turn affect their functionality. One of the primary advantages of MOFs is their exceptionally high surface area and tuneable porosity, which allow for efficient drug loading and storage of therapeutic agents. This adjustable pore size can be precisely engineered to accommodate various drug molecules, enabling controlled release profiles that respond to specific physiological conditions. Additionally, their customizable multifaceted structures with multiple metals (such as mono-, bi-, or tri-metallic systems) and/or organic linkers allows for the use of conformationally flexible linkers and/or geometrically adaptable inorganic building units as well as for functionalization with targeting ligands or biomolecules, enhancing specificity towards diseased tissues or cells, such as cancer. 58 Moreover, certain MOFs, such as those belonging to the class of ‘‘PCN’’ can be used for specific applications in photodynamic therapy (PDT) and photothermal therapy (PTT). The myriad combinations of metal nodes and organic linkers offer an almost boundless array of possibilities for creating MOFs.However,eventhoughthestructuresofMOFsreportedto date exceed 100k units, only a limited number of MOF classes have been investigated for biomedical applications. 59 This limitation mainly arises from the complexities of the pharmacokinetics of MOFs, in terms of absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox or ADMET), which narrow down the pool of MOFs suitable for designing nanocarriers. 60 Unfortunately, a comprehensive understanding of the ADME-Tox of MOFs, remains elusive, leading to the selection of MOFs for biological applications based on rough and more general criteria. In this regard, a recent review delves deeply into the ADMET of nanoparticles in general, emphasizing the ongoing need for further investigation into this practically unknown area. 61 Currently, the types of MOFs used to prepare CHs-MOFs mainly belong to the UiO, ZIF, PCN, MIL, and CD-MOF families, whose key characteristics are summarized in Fig. 3. Designing CHs-MOFs Features When designing MOFs-CHs, a sequence of characteristics should be considered, including biological compatibility, such as toxicity, biodegradability, and chemical stability, sizeand shape-controlled synthesis, as well as surface and pore volume versatility. Toxicity: CHs-MOFs should exhibit low toxicity per se, and their degradation products, i.e., the metal nodes and the organic components, should also be biocompatible. This implies the use of metals with low toxicity, such as those naturally occurring in the body like magnesium, calcium, and some dblock transition metals (e.g., iron, cobalt, manganese, copper, zinc, molybdenum), as well as other metals known for their relatively low toxicity such as zirconium and titanium. Regarding the organic components, i.e., the organic linkers and the CHs (as long as the CHs themselves do not serve as organic linkers), a variety of compounds ranging from fumaric acid and terephthalic acid to porphyrin-based linkers are commonly employed, alongside natural compounds like adenine, aspartate, or cyclodextrins. Importantly, the lethal dose 50 values (LD 50 ) for these types of metal and ligands are substantially high (i.e. their toxicity is low). For example, the LD 50 of Cu is 25 mg kg 1 ,that of terephthalic acid is 5 g kg 1 , and that of b-CD is ca. 18 g kg 1 . These values are even less impactful given the minimal amounts of metals and ligands required to prepare the few milligrams of CHs-MOFs used in biomedical applications. Chemical stability and biodegradability: CHs-MOFs should also show the right balance between being chemically stable and biodegradable. They should remain stable in biological fluids until they reach their target site but break down within a certain timeframe (few hours/days) to avoid accumulating in the body. The biodegradation can also happen in response to external triggers, like changes in pH or the presence of specific enzymes found in certain parts of the body, like certain types of tumours. Currently, researchers are running into more challenges with CHs-MOFs stability compared to their biodegradability. This is particularly evident when CHs-MOFs are exposed to solutions simulating the human body, such as phosphate solutions (e.g., PBS, pH 7.4) or artificial lysosomal fluid (ALF, pH 4.4). The stability in PBS is particularly challenging since phosphate ions have good affinity towards some metal ions/clusters, thus they tend to replace the organic ligands. To tackle this, Review Nanoscale Horizons Open Access Article. Published on 04 November 2024. Downloaded on 5/15/2025 8:42:36 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online 262 | Nanoscale Horiz., 2025, 10, 258–278 This journal is © The Royal Society of Chemistry 2025 some approaches involve the introduction of structural defects with specific organic compounds, such as in the case of the utilization of amino terephthalic acids in UiO-66, or coating MOFs with long-chain molecules like poly ethylene glycols (PEGs) or polysaccharides. Shape and size: when discussing the shape and size of nanoparticles for biomedical applications, which are crucial for the circulation in the body and ability to penetrate cells, especially for targeting applications, the literature offers a complex range of perspectives and sometimes conflicting Fig. 3 Structures and relevant features of the most studied MOFs for the preparation of CHs-MOFs. Nanoscale Horizons Review Open Access Article. Published on 04 November 2024. Downloaded on 5/15/2025 8:42:36 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry 2025 Nanoscale Horiz., 2025, 10, 258–278 | 263 opinions regarding the ideal nanocarrier. A point of agreement is that particles with a hydrodynamic diameter (HD) smaller than 5.5 nm are swiftly eliminated via urinary excretion and particles should ideally be smaller than 200 nm to evade detection by the mononuclear phagocyte system. Therefore, nanosystems for biomedical applications should ideally fall within a hydrodynamic (HD) size range of 5.5–200 nm, ensuring that any potential agglomerates do not obstruct the smallest blood vessels in the body, i.e., the capillaries. In alignment with the current literature, the majority of CHs-MOFs are indeed prepared with sizes below 200 nm. However, investigations into how the shapes and sizes of CHs-MOFs influence their dynamics in bodily fluids and, more generally, their ADMET profile are rarely conducted. Consequently, the selection of shape and size is primarily based on reported literature, even when referring to other types of MOFs or nanoparticles. This underscores the need for further research in this largely unexplored area. Morphological characteristics: in order to be used as efficient drug carriers, MOFs for preparing CHs-MOFs are also selected based on their pore types and volume. Generally, the larger the pore volume, the greater the capacity for drug loading, including the accommodation of large molecules. Additionally, the choice of MOFs depends on their versatility in modifying both external and internal surfaces. For example, pores can be made hydrophobic to load hydrophobic drugs (if they are not already), or the external surface can be functionalized with ligands for targeted delivery. Synthetic strategies for CHs-MOFs As illustrated in Fig. 1, CHs-MOFs are prepared using two main approaches: post-synthetic modification (PSM), which includes physical adsorption and chemical conjugation, forming CHs-onMOFs, and incorporation during MOF synthesis, either through encapsulation, forming CHs@MOFs, or using CHs as building units coordinated with metal nodes or ions. Regardless of the chosen synthetic strategy, CHs-MOFs are synthesized using widely adopted techniques for producing MOFs in biomedical applications. These methods are summarized in Table 1, outlining the key advantages and disadvantages of each. In terms of PSM techniques, a straightforward approach involves immobilizing CHs onto MOF surfaces through physical adsorption. However, this method is constrained by the structures and pore sizes of the MOFs, as well as by the weak Table 1 Main synthetic techniques for the preparation of MOFs Synthetic methodology Features Advantages Limitations Example of MOFs Solvothermal – High temperature and/or pressure – High-quality, crystalline MOFs – Long reaction times – UiO-66 – Solvent-driven crystallization – Tuneable size and porosity – Energy-intensive – HKUST-1 – Use of solvents – PCN-222 Hydrothermal – Water as the solvent – Environmentally friendly – Limited to water-soluble precursors – MIL101(Fe) – High pressure – Lower toxicity – Less control over pore size and crystallinity – ZIF-8 – Cost-effective Microwave-assisted – Rapid heating – Fast reaction – Limited scalability – CD-MOFs – Uniform energy distribution – Energy-efficient – Expensive setup – Short reaction time – Uniform crystal growth – Control to avoid uneven heating Electrochemical – Involves electrochemical reduction of metal ions – No solvents or additives needed – Limited range of MOFs – MIL101(Fe) – Room temperature – High crystallinity – Requires specialized equipment – Fast and energy-efficient – Poor scalability Mechanochemical – Uses mechanical force to induce reactions – Solvent-free – Limited range of MOFs – HKUST-1 – Solvent-free or minimal solvent use – Fast and cost-effective – Lower crystallinity and porosity – Simple equipment Sonochemical – Ultrasonic waves create localized highenergy conditions to drive the reaction – Short synthesis time – Requires specialized equipment – ZIF-67 – High crystallinity – Difficult to scale up – Can improve yields Spray-drying – Aerosolized droplets to form MOF particles in a continuous flow system – Rapid synthesis – Limited control over crystallinity – UiO-66 – Scalable for industrial applications – Not ideal for producing highly crystalline MOFs – ZIF-8 – Potential for producing uniform particles Microemulsion technique – Microemulsions are the reaction media containing metal ions and organic linkers – Control over particle size and morphology – Requires careful optimization of surfactants and conditions – ZIFs – Facilitates the synthesis of nanostructured MOFs – Challenges in scalability – Can be performed under mild conditions Vapor diffusion method – Diffusion of vapor phases to promote crystal growth – Mild conditions – Slow crystallization – UiO-66 – Potential high-quality crystals – Difficult to control the nucleation – CD-MOFs Review Nanoscale Horizons Open Access Article. Published on 04 November 2024. Downloaded on 5/15/2025 8:42:36 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online 264 | Nanoscale Horiz., 2025, 10, 258–278 This journal is © The Royal Society of Chemistry 2025 interactions between the MOFs and CHs (VdW and electrostatic), which are easily broken. Alternatively, CHs can be linked to MOFs via chemical conjugation techniques, allowing for the formation of stronger bonds (such as hydrogen, ionic, or covalent bonds). This can be achieved by functionalizing MOFs with specific groups, utilizing building units already containing these groups, such as aminoterepthalic acid instead of terepthalic acid, or by modifying the MOF surface with additional compounds. The latter method may involve anchoring organic ligands, such as PEGs, with one end having an affinity for the MOF (e.g., phosphate or sulfate) and the other end capable of linking to carbohydrates, such as azides for click chemistry. Regarding the incorporation of CHs during MOF synthesis, the first approach involves synthesising the MOF in a solution containing CHs, leading to their encapsulation or embedding within the MOF structure. Alternatively, CHs can serve as fundamental building blocks for constructing bio-MOFs, acting as organic ligands coordinated with metal nodes, as in the case of cyclodextrin-based MOFs (CD-MOFs). To rigorously prove and thoroughly investigate the effective formation of CHs-MOFs, a comprehensive sequence of characterization techniques is essential. However, despite the critical importance of these techniques, many studies in the literature employ only a subset, thereby limiting the full characterization of CHs-MOFs and hindering their potential exploitation. Among all, infrared/Raman spectroscopy is used to identify functional groups and assess interactions between CHs and the MOFs. X-ray photoelectron spectroscopy (XPS) offers information about the elemental composition and chemical states of the loaded materials, allowing the loading of CHs to be quantified, and an understanding of their bonding with the MOFs. Energy dispersive X-ray spectroscopy (EDX) coupled with scanning electron microscopy (SEM) provides imaging and elemental analysis at the microstructural level, revealing the distribution of CHs within the MOF matrix. Inductively coupled plasma mass spectrometry (ICP-MS) is instead employed to determine the concentration of metal ions and assess the overall composition, ensuring the integrity of the MOF structure after loading. Nuclear magnetic resonance (NMR) spectroscopy can provide detailed information about the local environment of the CHs, helping to confirm their incorporation into the MOF structure and elucidate their interactions at the molecular level. PSM. In a first approach for preparing CHs-on-MOFs by PSM, different CHs can be deposited onto the MOF surfaces, or, in other words, the MOF can be coated with CH. 35 This requires a post-synthetic treatment, in which the CHs are employed as functionalising agents of the previously-synthesized MOF. 62 This can be done directly using a specific CH, a modified CH with selected functional groups, or by using ligands or molecules containing CHs. The interaction between this functionalising agent and the MOF surface can thus be of low/medium energy, including hydrophilic and hydrophobic interactions, hydrogen bonds, electrostatic and VdW, but also of covalent nature. 63 When the formation of covalent bonds is not required, the functionalizing of the MOFs is mainly based on the diffusion of the CH (or modified CH, or ligand with CH) to the surface of the MOFs in a solution, sometimes under mixing. Polysaccharides/glycans such as chitosan, hyaluronic acid and heparin can directly be used, thanks to the chemical groups or charge showing affinity for the MOF surface. In general terms, the functionalization of MOFs with high molecular weight polysaccharide provides them with additional stability and may prevent MOF degradation. 35 Among all, hyaluronic acid (HA) is one of the most studied polysaccharides for the preparation of CHs-onMOFs, and can be incorporated onto the MOF surface by a simple chelation reaction thanks to the large amount of carboxyl groups, resulting in NPs with improved tumour targeting ability, blood circulation time and biodistribution. HA is particularly noteworthy for its targeting abilities, especially in the context of cancer cells, including triple-negative breast cancer (TNBC). 64 For example, the functionalization with HA has been reported for the Zrbased porphyrinic MOF PCN-224 (Fig. 4(A)), 51 PCN-222, 65 MIL100(Fe), 66 and ZIF-8. 67 In these cases, the loading of the MOF NPs with HA acid gives rise to a drug carrier to target cancer cells overexpressing CD44 receptor. 68 The coating with HA has been also performed with a Zr clusters-thiazolothiazole based MOF, 68 and a Fe 2+ -based MOF, the latter associated with an electrostatic adsorption. 69 HA can also be incorporated onto polydopamine-coated MOFs, via aFe 3+ -mediated coordination reaction, as reported for a Zn-based ZIF-8 MOF. 70 Carboxymethyl cellulose and its derivatives can also be used to enhance the stability and biocompatibility of MOFs. This is the case for MIL-100(Fe) covered by carboxymethyl-dextran capable of specific targeting and killing of HER2/neu-positive cancer cells in vitro. 73 With a similar approach, a Cu-based MOF was also covered with carboxymethylcellulose, to provide better protection against the stomach acid environments and a high stability of drug dosing of ibuprofen, used as an oral model drug. 74 CHs containing sulfate groups can be used in certain cases for the coating of MOFs, provided that these groups interact with the metal centres of the MOF. An example is the case of heparin, a GAG containing numerous sulfate groups, that was absorbed on iron at defect sites in the MIL-101(Fe) in a postsynthesis step (Fig. 4(B)), giving rise to a composite biomaterial with good anticoagulant activity. 71 Analogously, folic acid conjugated chitosan, a semi-synthetically derived amino polysaccharide with cationic character, has also been used for the functionalization of the Zr-based MOF-808, after the incubation of the modified polysaccharide with the MOF. 75 In other cases, the CH is incorporated into an organic ligand, often of polymeric nature, which can be later attached to the MOF structure. For example, a poly(acrylic acid-mannose acrylamide) (PAAMAM) glycopolymer containing mannose was incorporated into MOF-808, a Zr-linked MOF. This glycopolymer was synthesised via RAFT polymerization of D-mannose acrylamide and acrylic acid, and contains a high number of carboxylate moieties to coordinate to the Zr 6 units at the particle surface (Fig. 4(C)). The final NPs were obtained after incubation of the MOF and the glycopolymer in methanol. This was reported to be associated with an increase in the NP cellular uptake. 27 Nanoscale Horizons Review Open Access Article. Published on 04 November 2024. Downloaded on 5/15/2025 8:42:36 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry 2025 Nanoscale Horiz., 2025, 10, 258–278 | 265 Some monosaccharides can also be attached to the surface of MOFs through chemical or electrostatic interactions. The incorporation of these compounds is particularly advantageous for targeting various overexpressed receptors, thereby enhancing the cellular uptake of nanoparticles by facilitating endocytosis and the effective internalization of therapeutic agents. Importantly, most CHs-MOFs made with monosaccharides, especially those designed for targeting applications, primarily utilize commercially available CHs directly linked to the MOFs, or employ short chemicals as linking agents, without further modifications. While this approach has driven valuable research and contributed to the advancement of innovative nanosystems, it also poses a limitation on ground-breaking discoveries. It does not fully leverage the rich chemistry of CHs for more efficient and selective targeting. Indeed, using simple monosaccharides does not guarantee optimal bio-interactions with targets, which often require substantial chemical modifications, such as the introduction of more polar or nonpolar functional groups. Furthermore, the absence of specific spacers between the monosaccharides and the MOFs creates significant steric hindrance, further reducing selectivity to targeting sites. This is the case, for example, of a MOF consisting of Gd 3+ nodes and 5-boronobenzene-1,3-dicarboxylic acid (BBDC) functionalised with glucose (Fig. 4(D)). 72 This nanoplatform was used for imaging-guided precise chemotherapy by interaction with glucose-transported protein (GLUT1) overexpressed in cancer cells. Similarly, Fe 3 O 4 NPs were first coated with the NH 2 -MIL-100 MOF, and this hybrid system was subsequently incubated with D-mannose in phosphate buffered saline. The monosaccharide was eventually absorbed onto the nanostructure surface, very likely driven by an electrostatic interaction, and this nanosystem was used for the targeted therapy of tumour cells exhibiting high levels of mannose receptor (MR) expression. 76 In another work, a novel CaCu-MOF was firstly loaded with doxorubicin and ovalbumin, thus covered and functionalized by galactosaminelinked HA (Fig. 5(C)). The presence of HA guaranteed the biocompatibility and stability of the MOF, while the galactosamine was aimed at the targeting of the asialoglycoprotein receptor (ASGPR) overexpressed on hepatic cancer cells. 77 In all Fig. 4 Examples of CH-on-MOF nanostructures. (A) Coating of the PCN-224 nanoMOF with HA, via their carboxylate groups. Taken from ref. 51 and reproduced with permission from the American Chemical Society, copyright 2019. (B) Heparin is able to complex with the metal sites of the MIL-101(Fe) MOF thought its sulfate groups. Taken from ref. 71 and reproduced with permission from the Royal Society of Chemistry, copyright 2018. (C) A poly(acrylic acid-mannose acrylamide) (PAAMAM) glycopolymer containing carboxylate groups is used for the functionalization of the MOF-808. Taken from ref. 27 published by the American Chemical Society, copyright 2022. (D) Synthesis of a MOF-glucose nanocarrier loaded with DOX. Taken from ref. 72 and reproduced with permission from the American Chemical Society, copyright 2018. Review Nanoscale Horizons Open Access Article. Published on 04 November 2024. Downloaded on 5/15/2025 8:42:36 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online 266 | Nanoscale Horiz., 2025, 10, 258–278 This journal is © The Royal Society of Chemistry 2025 these examples, no chemical modification of the monosaccharides was performed (except for those required to link them to the MOFs), nor were any specific spacers used between the monosaccharide and the MOF. This limitation affects targeting capabilities. For instance, in the case of targeting the ASGPR, it has been demonstrated that the structural characteristics of the monosaccharides are critical for interaction with the Cterminal carbohydrate recognition domain (CRD) of ASGPR. Specifically, the CRD of ASGPR comprises the amino acids aspartic acid 241, aspartic acid 265, asparagine 264, glutamic acid 252, glutamine 239, and tryptophan 243. 78 CHs binding is initiated by the coordination of specific amino acids in the Fig. 5 Molecular interactions between (A) galactose, and (B) N-acetyl-galactosamine (GalNAC) at the active binding site (CRD) of ASGPR. (C) The preparation of HA-galactosamine for the functionalization of CaCuMOF. 77 (D) Synthetic strategy for the preparation of a ligand based on N-acetylgalacosamine and sulphated PEG for the functionalization of PCN-222. 11 Nanoscale Horizons Review Open Access Article. Published on 04 November 2024. Downloaded on 5/15/2025 8:42:36 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry 2025 Nanoscale Horiz., 2025, 10, 258–278 | 273 MOFs modified with specific ligands, including hyaluronic acid, to target CD44 receptors in tumour cells. Similarly, CN108187046B reports a MOF shielded with hyaluronic acid that can carry curcumin for both cancer diagnosis and treatment. Some other patents are related to CD-MOFs, such as US10583147B2, US9085460B2, CN107151329B, and CN107837401B. For example, US10125016B2 reports a method for the environmentally friendly synthesis of CD-MOFs, and US10500218B2 describes loading different drugs into CD-MOFs for biomedical applications. However, despite the tremendous potential of CHs-MOFs and the burgeoning focus in the field, many challenges and limitations must be addressed to shift academic R&D results to real-world biomedical applications: 1. Scalability and reproducibility: firstly, substantial technical challenges related to the large-scale preparation of MOFs for biomedical applications need to be addressed. This includes achieving good reproducibility and yields of size-controlled MOF nanoparticle synthesis. These challenges are compounded by the poor understanding and modelling of MOF crystallization, from seed formation to growth. 121 Currently, most MOF-related papers are limited to synthesizing only dozens of milligrams or few grams per batch, and larger-scale productions are rarely considered, 122,123 and are practically unreported for biomedical applications. 124 This limitation should also be addressed when using intensified processes, such as continuous flow synthesis, as well as other innovative technologies like microwave and ultrasound-assisted synthesis, which are typically explored for their potential to scale-up but rarely demonstrated effectively for this purpose. 125,126 Reaching reliable, large-scale production methods is essential for translating CHs-MOFs from research to clinical applications. 2. Size control: achieving precise control over the size of CHs-MOFs is difficult, as size distribution is often influenced by kinetic factors, which are harder to scale up than thermodynamic control. Many studies in the literature do not address the size distribution of the produced CHs-MOFs, and only a few have investigated how various experimental conditions impact their shape and size. For example, the first study on the effect of the different parameters on the shape and size of PCN-222 was only recently reported. 11 Furthermore, as mentioned earlier, the impact of the size of CHs-MOFs on ADMET should be thoroughly explored, potentially using advanced computational techniques such as machine learning (ML). 3. Sustainability characteristics: the sustainable production of MOFs should be considered, as current preparation methods are typically energy and solvent-consuming. For example, MIL101(Fe) and PCNs are produced using DMF (N,N-dimethylformamide), 125,126 a highly toxic and potentially carcinogenic solvent. Although some articles have recently discussed environmentally friendly MOF synthesis for biomedicine, opening the research to this type of investigation, requires much more effort, including green metrics 127–129 and life cycle assessment (LCA) calculations. 130 Atthesametime,thewell-establishedchemistry of carbohydrates and the production of CH-based drugs, considering the green principles of chemistry, is an advantageous point in developing CHs-MOFs. However, only a few monosaccharides have been exploited to produce CHs-MOFs, with polymeric CHs being more commonly selected. This implies limited chemical control, and the effect of different sizes of CH-polymers on biointeractions within CHs-MOFs is not well understood. 131 Natural ligands should also be more extensively considered as tools for functionalizing MOFs with CHs, as demonstrated recently with a lecithin-based ligand used for the functionalization of MOFs with D-mannose. 132 4. Biological interactions between CHs and MOFs: the synergy between CHs and MOFs in biological systems remains poorly understood. Investigating how these two components interact, both at the molecular level and within living organisms, is crucial for maximizing their therapeutic efficacy and ensuring their safe use. These interactions influence key factors such as targeting capabilities, biodegradability, and long-term stability in biological environments. Therefore, significant effort is required to investigate bio-CHs-MOFs interactions and design more appropriate and efficient systems, including Fig. 9 (A) B: Alterations in nuclear DNA: (i) quantitative results for the number of apoptotic cells per 100 total cells, (ii) microscopic images illustrating nuclear fragmentation, DNA nicks, and nuclear deformities. Reprinted and adapted from ref. 115 with permission from Elsevier, copyright 2022. (B) Schematic illustration of the construction of Gal-ANI-on-ZnAP and its application for synthetic lethal therapy and visualization therapy adapted from ref. 110. Review Nanoscale Horizons Open Access Article. Published on 04 November 2024. Downloaded on 5/15/2025 8:42:36 AM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online 274 | Nanoscale Horiz., 2025, 10, 258–278 This journal is © The Royal Society of Chemistry 2025 specifically-modified CHs for targeting, and precise linkers/ spacers for the modification of MOFs, similarly to what is carried out with other types of NPs. 57,133,134 This will require an interdisciplinary approach, combining expertise from materials chemistry, organic chemistry, biology, and computational chemistry. While this approach is still largely unexplored, it has great potential for advancing the field. In addition, there are specific limits related to the different methods used to prepare the CH-MOFs, that needs to be implemented. In particular: CHs-on-MOFs prepared through PSM by low/medium energy interactions. This simple technique avoids harsh conditions and complex synthetic procedures but results in less stable CHs-MOFs. However, CHs may be less stable than covalently linked ones, leading to leaching and decreased bioactivity over time. The process may also be less efficient due to a limited number of reactive sites, resulting in lower surface coverage and heterogeneous distribution of carbohydrates, leading to non-uniform properties. CHs-on-MOFs prepared through PSM by bioconjugation. CHs-MOFs produced this way are more stable, and it is easier to control the location of CHs within the MOF structure. This method offers versatility due to the wide range of available MOFs and various methods for modifying MOF surfaces. Despite these strengths, grafting presents challenges, such as ensuring covalent bond formation does not disrupt the MOF structure or compromise its properties. The synthesis process is often more complicated and time-consuming, requiring precise control over reaction conditions and purification methods. CHs@MOFs prepared via encapsulation. This method results in more durable CHs-MOFs. However, encapsulation is limited to a few CHs. The synthesis can also be challenging due to potential side reactions between CHs and the other reagents. Additionally, the stability and reproducibility can be problematic, with weak interactions potentially leading to desorption of CHs-MOFs over time. CHs-MOFs prepared using CHs as building blocks. This strategy is practically limited to cyclodextrin-MOFs, which are also water-soluble and thus have limited applicability for biomedical applications unless appropriately modified. The use of other types of carbohydrates to obtain crystalline MOFs remains an open challenge. As a result, ongoing research should focus on addressing these challenges alongside new research on CHs-MOFs, potentially leading to a new era in biomedical applications. In this context, the development of CHs-MOFs is greatly enhanced through various advanced synthesis and characterization techniques that optimize the interaction between carbohydrates and MOFs, thereby improving their biomedical applications. Techniques such as layer-by-layer (LbL) assembly provides precise control over MOF coatings for applications in biosensing or drug release, and green synthesis approaches emphasize environmental sustainability by utilizing renewable materials and non-toxic solvents. Click chemistry enables efficient functionalization of MOFs with carbohydrates, enhancing their biological functionality, while electrochemical synthesis allows for precise control of reaction conditions to optimize carbohydrate interactions. Additionally, high-throughput screening and computational design techniques accelerate the discovery and development of CHs-MOFs by enabling rapid testing and predictive modelling. Together, these methods offer a comprehensive framework for fine-tuning CHs-MOFs properties, addressing challenges related to stability, scalability, and biocompatibility for applications such as drug delivery and biosensing. The search for smart, innovative solutions to the preparation of novel CHs-MOFs could pave the way for real-world biomedical applications. Despite over 100 000 MOF structures being catalogued in the Cambridge Structural Database (CSD), and the theoretical number of possible MOF structures being nearly limitless, only two MOFs have entered human trials to date. 135 This limited transition to industrial production, coupled with ongoing debates about its efficiency, leaves room for ground-breaking discoveries, inviting the smartest and most creative researchers to push the boundaries of CHs-MOFs development. Data availability This is a review manuscript and does not contain any primary data. All data discussed and analyzed in this review are derived from previously published studies, which are appropriately cited in the manuscript. Therefore, no new data were generated or analyzed in support of this work. The cited references provide the source of all data presented. If additional information is needed, readers are encouraged to refer to the original publications listed in the reference section. Conflicts of interest There are no conflicts to declare. Acknowledgements Financial support was provided by the Andalusian Ministry of Economy, Science and Innovation in the framework of the Plan Andaluz de Investigacio ´n, Desarrollo e Innovacio ´n(PAIDI2020, programme 54  a ‘‘Investigacio ´ncientı ´fica e innovacio ´n,’’ ‘‘POSTDOC_21_00594’’), the Spanish Ministry of Science and Innovation (Ref: PID2020-119949RB-I00), the Andalusian Ministry of Economy, Science and Innovation cofinanced by the European Regional Development Fund (ERDF) from FEDER and the European Social Fund (ESF) (PY20_00882 and CV20-04221). 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