Onco-receptors targeting in lung cancer via application of surface-modified and hybrid nanoparticles: a cross-disciplinary review

processes Review Onco-Receptors Targeting in Lung Cancer via Application of Surface-Modified and Hybrid Nanoparticles: A Cross-Disciplinary Review Fakhara Sabir 1, Maimoona Qindeel 2,3, Mahira Zeeshan 3, Qurrat Ul Ain 4, Abbas Rahdar 5,* , Mahmood Barani 6, Edurne González 7and M. Ali Aboudzadeh 8,9,*   Citation: Sabir, F.; Qindeel, M.; Zeeshan, M.; Ul Ain, Q.; Rahdar, A.; Barani, M.; González, E.; Aboudzadeh, M.A. Onco-Receptors Targeting in Lung Cancer via Application of Surface-Modified and Hybrid Nanoparticles: A Cross-Disciplinary Review. Processes 2021,9, 621. https://doi.org/ 10.3390/pr9040621 Academic Editor: Carla Vitorino Received: 1 March 2021 Accepted: 29 March 2021 Published: 1 April 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 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/). 1Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, 6720 Szeged, Hungary; [email protected] 2Hamdard Institute of Pharmaceutical Sciences, Hamdard University Islamabad Campus, Islamabad 76400, Pakistan; [email protected] 3 Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; [email protected] 4Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, Bandung Institute of Technology, Bandung 40132, Indonesia; [email protected] 5Department of Physics, University of Zabol, Zabol 98613-35856, Iran 6Department of Chemistry, Shahid Bahonar University of Kerman, Kerman 6169-14111, Iran; [email protected] 7POLYMAT and Kimika Aplikatua Saila, Kimika Fakultatea, University of the Basque Country UPV/EHU, Joxe Mari Korta Zentroa, Tolosa Hiribidea 72, 20018 Donostia, San Sebastián, Spain; [email protected] 8Centro de Física de Materiales, CSIC-UPV/EHU, Paseo Manuel Lardizábal 5, 20018 Donostia, San Sebastián, Spain 9Donostia International Physics Center (DIPC), Paseo Manuel Lardizábal 4, 20018 Donostia, San Sebastián, Spain *Correspondence: [email protected] (A.R.); [email protected] (M.A.A.) Abstract: Lung cancer is among the most prevalent and leading causes of death worldwide. The major reason for high mortality is the late diagnosis of the disease, and in most cases, lung cancer is diagnosed at fourth stage in which the cancer has metastasized to almost all vital organs. The other reason for higher mortality is the uptake of the chemotherapeutic agents by the healthy cells, which in turn increases the chances of cytotoxicity to the healthy body cells. The complex pathophysiology of lung cancer provides various pathways to target the cancerous cells. In this regard, upregulated onco-receptors on the cell surface of tumor including epidermal growth factor receptor (EGFR), integrins, transferrin receptor (TFR), folate receptor (FR), cluster of differentiation 44 (CD44) receptor, etc. could be exploited for the inhibition of pathways and tumor-specific drug targeting. Further, cancer borne immunological targets like T-lymphocytes, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and dendritic cells could serve as a target site to modulate tumor activity through targeting various surface-expressed receptors or interfering with immune cell-specific pathways. Hence, novel approaches are required for both the diagnosis and treatment of lung cancers. In this context, several researchers have employed various targeted delivery approaches to overcome the problems allied with the conventional diagnosis of and therapy methods used against lung cancer. Nanoparticles are cell nonspecific in biological systems, and may cause unwanted deleterious effects in the body. Therefore, nanodrug delivery systems (NDDSs) need further advancement to overcome the problem of toxicity in the treatment of lung cancer. Moreover, the route of nanomedicines’ delivery to lungs plays a vital role in localizing the drug concentration to target the lung cancer. Surface-modified nanoparticles and hybrid nanoparticles have a wide range of applications in the field of theranostics. This cross-disciplinary review summarizes the current knowledge of the pathways implicated in the different classes of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. Furthermore, it focuses specifically on the significance and emerging role of surface functionalized and hybrid nanomaterials as drug delivery systems through citing recent examples targeted at lung cancer treatment. Processes 2021,9, 621. https://doi.org/10.3390/pr9040621 https://www.mdpi.com/journal/processes Processes 2021,9, 621 2 of 37 Keywords: lung cancer; nanoparticles; toxicity; surface modification; hybrid nanocarriers 1. Introduction Lung cancer is one of the most prevalent diseases and the leading causes of death worldwide [ 1 ]. It is more common in males than in females and based on an estimation, this type of cancer caused 154,050 deaths in 2018 [ 2 ]. One of the most common causes of this devastating disease is chronic tobacco usage. The major reason for its high mortality is the late diagnosis of the disease, and in most cases, lung cancer is diagnosed at the fourth stage when the cancer has already metastasized to the nearby organs [ 3 ]. Among lung cancer patients, 85% exhibit nonsmall cell lung cancer (NSCLC) while the rest (15%) of the patients have small cell lung cancer (SCLC). The survival of the patients suffering from lung cancer mainly depends upon the early diagnosis and efficient surgical removal of the tumor tissues. Among the different treatments, chemotherapy is the most recommended therapy to treat lung cancer. However, the major limitation of conventional chemotherapy is related to the presence of inefficient drugs at the target site, which ultimately compromises the therapeutic efficacy [ 4 ]. To reduce this problem, repeated administration of systemic chemotherapy at higher concentrations is required, which is allied with dose-related systemic toxicities. Moreover, in conventional therapies the uptake of the cytotoxic agents by the healthy cells can increase the chances of cytotoxicity in these normal cells. Hence, novel approaches are required for both the diagnosis and treatment of lung cancers [5]. Due to numerous limitations associated with these conventional methods, several researchers have exploited nanotechnology-based approaches for the efficient diagnosis and delivery of therapeutic agents [ 6 ]. Among various nanoparticle-mediated drug delivery systems, the most frequently used ones for lung cancer treatment include polymeric nanoparticles [ 7 , 8 ], liposomes [ 9 , 10 ], bionanoparticles [ 11 , 12 ] and metallic nanoparticles [13,14]. These nanoparticles have been very effective due to their small size, large surface area, high biocompatibility and reduced renal clearance. Although the use of nanoparticles has shown several advantages [ 15 ], their site-specific delivery is still a problem for which passive and active-targeting approaches are necessary [16,17]. The passive targeting approach utilizes the exploitation of the enhanced permeability and retention (EPR) effect. In many disease conditions, including lung cancers, the endothelial lining of the blood vessels exhibits higher permeability than in normal conditions [ 17 , 18 ]. The presence of this leaky vasculature allows the higher permeation of the nanoparticles into the target site [ 19 ]. Moreover, the lack of a normal lymphatic drainage system in the tumor site contributes to higher levels of retention of the nanoparticles. However, this idiosyncratic property cannot be applied to low molecular weight drugs which have a small residence time and rapid excretion from the tumorous cells. Low molecular weight drugs can be encapsulated in unionized drug carriers to improve their pharmacokinetics (elongated systematic circulation), increasing tumor selectivity and lowering side effects. This phenomenon of tumor-targeting is called “passive” and depends upon the properties of the carrier molecule (its molecular weight and residence time) and the tumor anatomy (vascularity, porosity, etc.), but does not have any ligands for specific cells’ binding sites. The EPR effect provides a 20–30% higher concentration of the drug targeted delivery of the tumorous site compared to normal body tissues [20,21]. EPR effect is extremely dependent on the intrinsic pathways of tumor cells’ growth and it is controlled specifically by the rate of angiogenesis and lymphangiogenesis, the rate of perivascular tumor development, stromal thickness response and the intratumor pressure. All these elements, along with the physicochemical properties of nanoparticles, can influence the efficiency of the drug’s targeted delivery [ 22 ]. However, the extrusion properties of the newly formed tumor’s blood vessels have an impact on the nanomedicine impregnation; it causes an increase in the interstitial pressure, which may hinder the retention of the drug carriers in the tumor tissues. Furthermore, due to the imbalance Processes 2021,9, 621 3 of 37 between the proand antiangiogenetic signaling in different points of the tumorous tissues, the blood vessels are deviant with enlarged, curvy and saccular pathways, unorganized interconnection processes and branching. This miscellaneous blood circulation causes an irregular growth of the tumor cells and those cells surrounding the blood vessel grow rapidly compared to those that are far away, because of low oxygen and nutrition supply. This explains why the outer sites of large tumorous tissues have less blood supply (i.e., 1–2 cm in diameter in mice) and why is most often difficult for nanomedicines to reach the cores of tumor cells. Although the interstitial pressure is high in the inner portion of the tumor, the extrusion rate is unexpectedly small. This pattern was observed in some different types of murine and human tumor cells. The increased interstitial pressure does not only hinder the drug supply to the core tumorous tissues but also retards the growth of new blood vessels. This causes a higher blood supply to flow towards the tumor cells’ periphery, indicating that there is the possibility of modifying the EPR effect chemically or mechanically to improve the growth of the blood vessels for the retention of the drugloaded nanocarriers. It is worth mentioning here that some types of EPR enhancers like bradykinin (kinin), nitric acid, peroxynitrite, prostaglandins, etc. may cause hypertension that could enhance tumor extrusion [23]. To further improve the targeted delivery of the imaging modalities and therapeutic agents against lung cancer, many researchers have also exploited the receptor-mediated delivery of theranostics [ 24 ]. Several receptors are overexpressed in lung cancer, like oxytocin, vasopressin, chemokine, epidermal growth factor, bradykinins, bombsein, folate and tyrosine receptors. The majority of the lung cancer receptors are categorized as G-protein coupled receptors. These receptors have a potential role in the formation, progression and metastasis of lung cancer and are involved in angiogenesis process during tumor development and also during the progression of the cancer to the nearby organs [ 25 ]. The overexpression of several kinds of receptors in lung cancer has been exploited by researchers for the site-specific delivery of theranostics. As compared with the passive targeted approach, a higher amount of the drug can be made to reach the target site through active targeted delivery of the imaging modalities and therapeutic agents. Active targeting is compulsory for the proper distribution of drugs, genes and theranostics to the action site so the therapeutic effect on normal body tissue can be avoided. By using active targeting, a sufficient amount of drug is placed at the tumor site increasing the drug efficiency by many folds. Thus, active targeting nanosystems are more efficient than passive targeting ones. Active targeting is possible exclusively when the nanocarriers are enriched with ligands that are specific for the overexpressed receptors in lung cancers [ 26 ]. This phenomenon enhances the binding capacity of the drug and imaging modalities to the tumor tissues and thus increases the drug entrapment capacity at the tumor site. Hundreds of ligands and antibodies have been discovered against the abovementioned receptors and are exploited for targeted delivery of the drug cargoes to the target site. A strong ligand/receptor binding affinity serves as role model to promote active binding technology. This can improve the targeted delivery of theranostics and therapeutic agents on the one hand and overcome the problems allied with conventional approaches on the other hand [ 26 ]. The visual illustration of various nanotechnology-based theranostic delivery approaches are shown in Figure 1. Processes 2021,9, 621 4 of 37 Processes2021,9,xFORPEERREVIEW4of36   context,thisreviewcouldattracttheinterestofmedicalscientistswhoareinvolvedin biologicalsystems.Thesecondspecificfocusofthisreviewisontheroleofthesur‐ face‐modifiedandhybridnanomaterialsasdrugdeliverysystemsincombatinglung cancer.Thisspotlightwasachievedthroughcitingmosttherecentandrepresentative examplestargetedatlungcancertreatment.Fromthisperspective,itcouldbehighlyin‐ terestingformaterialscientists. Thefieldsofbiologyandmaterialsciencearetraditionallyratherseparated,asmuch astheynaturallyrelyontheverysamebasicprinciples.Throughthenovel cross‐disciplinaryfocusofthisreview,weattempttoovercomethisgapandcreatea moresynergeticperspectiveonbothareas,whichwillbehighlybeneficialforthescien‐ tificcommunitygiventheplethoraofdiscussionsanddiscoveriesthatcanbeenvisaged.  Figure1.Schematicpresentationofvariousmethodsfordeliveryoftherapeuticagentsagainstlungcancerincluding(A) polymericnanoparticle‐basedapproach,(B)metallicnanoparticle‐basedapproachand(C)bioparticle‐basedapproach. Figure 1. Schematic presentation of various methods for delivery of therapeutic agents against lung cancer including ( A ) polymeric nanoparticle-based approach, (B) metallic nanoparticle-based approach and (C) bioparticle-based approach. This review first summarizes the current knowledge of the pathways implicated in the different types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. The utilization of different targeting approaches to combat the toxicity of the chemotherapeutic agents is discussed here. The mechanism through which this targeted delivery is attained is also described. In this context, this review could attract the interest of medical scientists who are involved in biological systems. The second specific focus of this review is on the role of the surfacemodified and hybrid nanomaterials as drug delivery systems in combating lung cancer. This spotlight was achieved through citing most the recent and representative examples Processes 2021,9, 621 5 of 37 targeted at lung cancer treatment. From this perspective, it could be highly interesting for material scientists. The fields of biology and material science are traditionally rather separated, as much as they naturally rely on the very same basic principles. Through the novel cross-disciplinary focus of this review, we attempt to overcome this gap and create a more synergetic perspective on both areas, which will be highly beneficial for the scientific community given the plethora of discussions and discoveries that can be envisaged. 2. Pathways for Targeting Lung Cancer Lung cancer is histologically classified into NSCLC and SCLC. The complex interplay between pathological changes and oncogenic mutations alters the signaling of multiple pathways and the expression of chemokines and various receptors. In turn, a modified tumor microenvironment facilitates the growth, proliferation, angiogenesis, metastasis and survival of the cancer cells. Traditional treatment strategies for the lung cancer include chemotherapy, radiotherapy and surgical excision. However, conventional chemotherapeutic agents have compromised therapeutic efficacy owing to pharmacokinetic issues, solubility problems and nonspecific action in normal cells with resultant toxicities. Moreover, high drug doses, tumor-associated alteration of pathways and subsequent treatment with multiple therapies will contribute to the occurrence of tumor resistance against chemotherapeutic agents [ 27 ] Therefore, the focus is now laid on the suppression of upregulated pathways including EGFR, RAS-RAF-MEK-ERK/MAPK, JAK-STAT, PI3K/AKT/mTOR through newly designed, specifically targeted small molecule inhibitors and antibodies (Figure 2). For instance, specific EGFR inhibitor (erlotinib) and PI3K/AKT/mTOR inhibitor (everolimius) replaced the first-line chemotherapy [ 28 ]. The most common genetic mutations in the lung cancer, along with their mode of aberration and the associated small molecule inhibitors to target specific pathways, are mentioned in Table 1. Nevertheless, the small-molecule-mediated targeted therapy is relatively successful and increases survival rates but is prone to therapeutic failure because of cancer relapse, and increased drug resistances due to targeting site mutations [29]. Hence, developing a highly targeted drug delivery system for specific action into the tumorous cells at an optimal dose is of great necessity. Broadly, lung cancer can be targeted through either passive or active targeting mechanisms or both. Passive drug delivery follows a certain principle to be deposited into the lung tissues under the EPR effect. EPR is attributed to leaky vasculature and deteriorative epithelial integrity that allows residence and accumulation of small sized particles into the lung tumorous tissue [ 30 ], which act either as a carrier to deliver the drug or act directly as a therapeutic moiety. In passive targeting, particle size is the main determinant for distribution and deposition in the lungs. For instance, large particles around >5 µ m have fewer chances to concentrate and are mostly exhaled out of the lungs. Particles in the range of 1–5 µ m are phagocytosed by the alveolar macrophages and particles with size <1 µ m could be deposited in the alveolar cells with minimal clearance by the immune cells [31]. To achieve improved tumor-specific targeting and to avoid possible threats with dislocation and clearance of passively targeted delivery carriers, active targeting of overly expressed onco-receptors with specific ligands brings better outcomes [ 30 ]. The inhibition of overexpressed receptor functions through specifically targeting moieties modulates the expression of cancer projectors and improves drug action in the tumor-specific lung tissues. Various overexpressed receptors in the tumor microenvironment include EGFR, TFR, FR and CD44 receptor [ 32 ]. Tumor receptors and tumor-associated immune cells have a role in cancer growth, proliferation, metastasis and angiogenesis. Therefore, receptormediated targeting and immune cell targeting alter the onco-proteins’ expression and inhibit oncogenic pathways to stop cancer growth and progression. Processes 2021,9, 621 6 of 37 Processes2021,9,xFORPEERREVIEW5of36   2.PathwaysforTargetingLungCancer Lungcancerishistologicallyclassifiedinto NSCLC and SCLC .Thecomplexinterplay betweenpathologicalchangesandoncogenicmutationsaltersthesignalingofmultiple pathwaysandtheexpressionofchemokinesandvariousreceptors.Inturn,amodified tumormicroenvironmentfacilitatesthegrowth,proliferation,angiogenesis,metastasis andsurvivalofthecancercells.Traditionaltreatmentstrategiesforthelungcancerin‐ cludechemotherapy,radiotherapyandsurgicalexcision.However,conventional chemotherapeuticagentshavecompromisedtherapeuticefficacyowingtopharmacoki‐ neticissues,solubilityproblemsandnonspecificactioninnormalcellswithresultant toxicities.Moreover,highdrugdoses,tumor‐associatedalterationofpathwaysandsub‐ sequenttreatmentwithmultipletherapieswillcontributetotheoccurrenceoftumorre‐ sistanceagainstchemotherapeuticagents[27]Therefore,thefocusisnowlaidonthe suppressionofupregulatedpathwaysincludingEGFR,RAS‐RAF‐MEK‐ERK/MAPK, JAK‐STAT,PI3K/AKT/mTORthroughnewlydesigned,specificallytargetedsmallmol‐ eculeinhibitorsandantibodies(Figure2).Forinstance,specificEGFRinhibitor(erlotinib) andPI3K/AKT/mTORinhibitor(everolimius)replacedthefirst‐linechemotherapy[28]. Themostcommongeneticmutationsinthelungcancer,alongwiththeirmodeofaber‐ rationandtheassociatedsmallmoleculeinhibitorstotargetspecificpathways,aremen‐ tionedinTable1.Nevertheless,thesmall‐molecule‐mediatedtargetedtherapyisrela‐ tivelysuccessfulandincreasessurvivalratesbutispronetotherapeuticfailurebecause ofcancerrelapse,andincreaseddrugresistancesduetotargetingsitemutations[29]  Figure2.OncogenicsignalingpathwaysanddrugstargetingabnormalsignalingofEGFR,VEGFR,PI3/AKT/mTOR, RAS/BRAF/MAK,JAK/STATpathways.Reproducedfromthereference [27] . Hence,developingahighlytargeteddrugdeliverysystemforspecificactionintothe tumorouscellsatanoptimaldoseisofgreatnecessity.Broadly,lungcancercanbetar‐ getedthrougheitherpassiveoractivetargetingmechanismsorboth.Passivedrugde‐ liveryfollowsacertainprincipletobedepositedintothelungtissuesundertheEPRef‐ fect.EPRisattributedtoleakyvasculatureanddeteriorativeepithelialintegritythatal‐ Figure 2. Oncogenic signaling pathways and drugs targeting abnormal signaling of EGFR, VEGFR, PI3/AKT/mTOR, RAS/BRAF/MAK, JAK/STAT pathways. Reproduced from the reference [27]. Table 1. Most common mutations in lung cancers and their relevant mechanisms. Oncogene Aberration Activation Mechanism Type of Lung Tumor Targeted Drug Inhibitors References EGFR Gatekeeper or oncogene mutation/ Amplification Ligand binding → Activation of tyrosine kinase → phosphorylation of EGFR NSCLC, ADC Erlotinib, Gefitinib, Cetuximab, [33–35] EML/ALK Fusion Fusion of amino terminal of EML4 to intracellular kinase → ALK tyrosine kinase receptor rearrangement leads to activation NSCLC, ADC Lorlatinib, ensartinib, crizotinib, alectinib [34,36,37] BRAF Mutation/fusion/kinase duplication Autophosphorylation of kinase loop and MEK protein binding NSCLC, ADC Dabrafenib, Vemurafenib [34,38] PI3K Modified/Activated PIP2 and PIP3 phosphorylation → placement of serine threonine kinase AKT into membrane →PI3K phosphorylation NSCLC, SCLC LY294002, wortmannin [39–41] Processes 2021,9, 621 7 of 37 Table 1. Cont. Oncogene Aberration Activation Mechanism Type of Lung Tumor Targeted Drug Inhibitors References mTOR Activated PIP2 and PIP3 phosphorylation → placement of serine threonine kinase AKT into membrane → mTOR phosphorylation NSCLC, SCLC Ridaforolimus, Rapamycin, sirolimus [39,40] RAS Mutation Conversion of GDP to GTP to activate G-protein (RAS) receptor NSCLS, ADC Tipifarinib, Lonafarinib, salirasib, sorafenib [34,42] p53 Mutation/Deletion Inactivating of missense gene mutations ADC, SCLC Advexin (adenoviral vector) [33,43,44] MEK Activated RAS activation NSCLS, ADC Selumetinib, sorafenib, trametinib [45,46] c-KIT Overexpression Regulatory and functional c-KIT mutations →activation of protein kinase SCLC Imatinib, STI-571 (Gleevec) [47,48] VEGF Overexpression HIF-1 or EGR-1 upregulation →VEGF expression SCLC, NSCLS Bevacizumab [33,49,50] ROS1 Rearrangement Autophosphorylation NSCLS Crizotinib [51,52] Epidermal growth factor receptor (EGFR); small cell lung cancer (SCLC); nonsmall cell lung cancer (NSCLC); adenocarcinoma (ADC); phosphatidylinositide-3 kinase (PI3K); hypoxia-inducible factor-1 (HIF-1); early growth response-1 (EGR-1); guanine diphosphate (GDP); guanine triphosphate (GTP); vascular endothelial growth factor (VEGF); echinoderm microtubule associated proteinlike-4 (EML4); phosphatidylinositol 4,5-bisphosphate (PIP2); phosphatidylinositol 3,4,5-bisphosphate (PIP3). 3. Onco-receptor Targets in Lung Tumors and Vasculature 3.1. Epidermal Growth Factor Receptor (EGFR) The EGFR is a cell surface peptide receptor from the ErbB family of tyrosine kinase. It consists of the extracellular region with two homologous ligand-binding domains and two cysteine-rich domains, a single slanging transmembrane domain and an intracellular region comprising juxtamembrane, a tyrosine kinase domain and a regulatory region [ 53 ]. EGFR regulates growth, differentiation and migration of the alveolar and bronchial epithelial cells under normal conditions, while overfunctioning in cancer facilitates the proliferation, metastasis, and invasion of lung cancer cells [ 54 ]. EGFR is among the highly expressed onco-receptors in 85% of NSCLC, with negligible involvement in SCLC [ 55 ]. Various monoclonal antibodies (panitumumab, cetuximab) and tyrosine kinase inhibitors (erlotinib, gefitinib, lapatinib) are used to target EGFR to treat lung cancer [ 55 ]. Furthermore, antisense oligonucleotides, affibodies, peptides, and nanobodies worked to inhibit EGFR [ 56 ]. Recently, it has been observed that ligand anchored nanocarriers specifically bind to extracellular domains of EGFR to release the drugs intracellularly for the tumor-specific inhibition of the signaling pathway. Under this approach, biotinylated-EGF ligand-bound gelatin nanocarriers have delivered increased concentrations of cisplatin to the lung cancer cells and significantly reduced tumor volume via inhalation route [ 57 ]. Similarly, DNA aptamer conjugated chitosan-liposome complexes have delivered erlotinib specifically to the lung cancer cells via EGFR [ 58 ]. Additionally, monoclonal antibody linked polymeric nanoparticles have shown promising results against acquired EGFR-kinase resistance in cancer cell lines and could be designed to suppress EGFR resistant pathways in the lung tumor [ 59 ]. Ligand-bound nanocarriers favor site-specific tyrosine kinase inhibitors or Processes 2021,9, 621 8 of 37 monoclonal antibodies’ delivery to the lung cancer cells, reduce off-site toxicities and endosomal clearance, and improve therapeutic efficacy with sustained drug release rate. 3.2. Transferrin Receptor (TFR) Transferrin (TF) is a nonheme glycoprotein (~180 kDa), mainly responsible for iron (ferric ions) transport in the body [ 60 ]. Therefore, TFR (CD71) is expressed by the normal epithelial and immune cells. In tumors, the overexpression of TFR facilitates fast iron transport to accomplish the nutritional demand of the cancer cells. The expression of TFR in cancer cells is 10-fold higher than the expression in normal cells [ 54 ]. Overexpressed TFR can be targeted by the ligands including TF, ferritin and anti-TFR antibody, thus improving the tumor targeting efficiency of the carrier system. TFR is highly upregulated in lung cancer; about 88% of NSCLC cases have elevated TFR-1 levels [ 61 ]. In one study, the blocking of TFR through the anti-TFR antibody significantly retarded the cell proliferation of the lung adenocarcinoma cell lines [ 62 ]. Furthermore, TF conjugated doxorubicin (DOX) liposomes increased cellular internalization in A549 lung cancer cells compared to alveolar type I(ATI) and alveolar type II (ATII) cells [ 63 ]. Similarly, antibodies and peptides targeted TFR and inhibited tumor growth or induced apoptosis of the tumor cells [64]. 3.3. α. vβ3 Integrin Receptor Integrins belong to the transmembrane heterodimeric glycoproteins family, consisting of the 18 α and 8 β subunits [ 65 ]. Integrins are expressed in multiple forms in many tumor-associated cell types. In lung cancer, the integrins α v, α 5, β 1, β 3 and β 5 have been demonstrated to develop the survival and metastasis of cancer cells [ 66 ]. The role of integrins encompasses cell–matrix adhesion, the maintenance of cellular morphology, differentiation and proliferation [ 54 ]. About 82% of NSCLC cases have higher integrin expression, while only 13% of SCLC expressed integrins [ 67 ]. The widespread functions of integrins in lung cancer suggest that their inhibition could be beneficial in tumor targeting and therapy. It was demonstrated that the inhibition of the α v β 3 and α v β 5 integrins with targeted ligands can block the endothelial cell angiogenesis and tumor metastasis [ 66 ]. In this context, arginylglycylaspartic acid (RGD) peptide has the potential to target α v β 3 integrin, thus facilitating drug delivery to the lung cancer. In one study, RGD anchored poly(lactide-co-glycolide) (PLGA)-chitosan nanocarriers successfully delivered paclitaxel (PTX) specifically to lung cancer, while normal human bronchial epithelial cells with poor integrin expression had negligible cytotoxic effects of PTX [ 68 ]. Furthermore, cyclic peptide anchored formulation elevated the localized drug concentration and suppressed the tumor cells in the subcutaneous and orthotopic A549 xenograft mice models as compared to the free drug controls [69]. 3.4. Folate Receptors (FRs) FRs are from a family of glycoproteins (35–40 kDa) having a strong binding affinity for folic acid (FA). FRs are differentiated into four isoforms including FR α , FR β , FR γ and FR δ [ 70 ]. Normal human cells have a very low content of FRs, whereas FRs are overexpressed in a variety of tumor cells—the first two isoforms (FR α , FR β ) are the most common [ 70 , 71 ]. In NSCLC, FR α is overly expressed especially in adenocarcinoma [ 54 ]. Therefore, FA or FR monoclonal antibodies could serve as a ligand to target lung cancer. Folate can be conjugated to chemotherapeutic agents, microparticles, nanocarriers, lipidic systems and oligonucleotides to directly target FR-positive tumor cells. Folate-PEGmodified cytochrome c nanomicelles have demonstrated selective targeting and internalization by FR expressed on the HeLa cells compared to FR negative cell lines [ 72 ]. Similarly, DOX and small interfering RNA (siRNA) were loaded into folate-biotin conjugated starch nanoparticles for codelivery into human lung cancer cells (A549). Folate-mediated codelivery has shown enhanced cytotoxicity and reduced proliferation of the A549 cells. The cytotoxicity was competitively inhibited in the presence of free folate; further, the expres- Processes 2021,9, 621 9 of 37 sion of insulinlike growth factor 1 receptor (IGF1R) proteins was decreased through the treatment [73]. 3.5. Cluster of Differentiation 44 (CD44) CD44 is a cell-surface based glycoprotein receptor with a specific affinity for hyaluronic acid (HA). The binding of HA to the receptor regulates cell adhesion and the differentiation and migration of the normal cells [ 74 ]. In tumors, CD44 has the important functions of cell adhesion, growth, proliferation, metastasis and induction of the cancer cell resistance [ 74 , 75 ]. CD44 is highly upregulated in squamous cell metaplasia and NSCLC [ 76 ] and is involved in metastasis of NSCLC to the lymph node [ 77 ]. HA, as an anionic glycosaminoglycan and a polymeric ligand, can be anchored to the surface of the particles or itself is able to self-assemble to target the lung cancer [ 78 , 79 ]. For instance, HA anchored polyethyleneimine-PEG nanoparticles specifically delivered siRNA to lung cancer cells [ 78 ]. Furthermore, enzyme hyaluronidase-1 expressed heavily in the malignant tumors degraded HA, thus facilitating drug release from HA in the target cancer cells [80]. 3.6. Other Onco-Receptors Several other receptors are heavily expressed in the lung tumor microenvironment including luteinizing hormone-releasing hormone (LHRH) receptors [ 81 ], chemotactic chemokines receptor 4 (CXCR4) [ 82 ], fibroblast growth factor receptor [ 83 ], tyrosine kinase AXL receptor [ 84 ], vascular endothelial growth factor receptor (VEGFR) [ 85 ], death receptor/TNF-related apoptosis-inducing ligand-receptor (DR4/TRAIL-R1) [ 86 ], β 2-adrenergic receptors ( β 2-AR) [ 87 ] and lectin receptors [ 88 ]. Targeting these receptors through specific ligands can inhibit lung cancer survival, growth and metastasis. 4. Extracellular Nanovesicles in Targeting Lung Cancer The concept of applying nanoparticles for lung cancer targeting shares a lot of similarities with the function of extracellular vesicles (EVs). In this regard, we briefly review these particles in this section. EVs are cell-derived, membrane-bound particles known to mediate intercellular signaling and are sensitive in organ-specific metastasis. Depending on the biogenesis pathways or their subcellular origin and size, EVs are also referred to as apoptotic bodies, microvesicles or exosomes [ 89 – 91 ]. EVs confined from distinct body fluids transport immune response-related and immune-modulatory molecules. These molecules include proteins, lipids, and nucleic acids. Recent studies considered EVs as one of the main components in the tumor microenvironment. In the tumor microenvironment, the EVs are able to transport the biomolecules to the less malignant cells. As the result, the less malignant cells receiving the EVs may continue to show increased metastatic and migratory behavior [92]. Integrin receptors are enriched in small EVs and are major players in mediating EV functions. For example, α v β 3 integrin is upregulated during cancer progression and is known to account for the migration of cancer cells. These nanovesicles’ signaling is capable of modifying the tumor cell’s structure, characteristics and functionality, such as overcoming drug resistance [ 93 , 94 ]. In their study, Hoshino et al. demonstrated that the tumor-derived lung-tropic EVs carry integrins α 6 β 1 and α 6 β 4, which are favorably taken up by lung fibroblasts and surfactant protein C-positive epithelial cells. The authors demonstrated that the incorporation of EVs by lung resident cells enhanced the expression of the proinflammatory gene S100 and promoted the lung metastasis [95]. From the therapeutic perspective, EVs are novel drug delivery systems and have more biosafety and biocompatibility characteristics than other synthetic surface functionalized or hybrid nanoparticles. In this context, EVs can be divided into unmodified and modified EVs [ 96 ]. Similar to nonfunctionalized nanoparticles, unmodified EVs have shown less efficacy in various performed studies. Therefore, scientists are now developing modified EVs through the introduction of therapeutic molecules into EVs or modifying the surface components of EVs to enhance their efficacies in terms of tissue targeting and Processes 2021,9, 621 16 of 37 9. Different Types and Applications of Surface-Modified and Hybrid Nanoparticles for Targeting Lung Cancer Nanoparticles are included in the drug delivery systems to overcome certain issues such as low solubility and permeability related to tumor targeting. The most significant advantages of nanoparticles are their excellent loading capacity and high surface to volume ratios. Various organic and inorganic nanomaterials have emerged as novel tools for cancer diagnosis and therapy due to their unique characteristics. In this review, based on the main structural moiety of nanoparticle we broadly divide them into three types: organic nanoparticles, inorganic nanoparticles and hybrid nanoparticles. The combinatorial therapeutic approach via hybrid nanoparticles is discussed in a separate subsection too. 9.1. Organic Nanoparticles Organic nanoparticles can be defined as solid particles composed of organic compounds (mainly polymers, lipids or proteins). They have been widely studied for decades, presenting a large variety of materials and exciting applications in cancer therapies. There are many biopolymeric nanoparticles that are utilized in the drug delivery systems. For example, PLGA is a biodegradable copolymer approved by the US Food and Drug Administration (FDA) for use in distinct biological products. PLGA nanoparticles can be used to obtain extended and sustained delivery of therapeutic agents including protein, peptide, RNA, DNA and small molecules to their particular target sites [ 170 , 171 ]. As an example, Karra et al. developed cetuximab functionalized PLGA nanoparticles and loaded them with PTX. The results confirmed the in vitro targeting performance and enhanced the cellular internalization along with cytotoxicity of this targeted delivery system in lung cancer cells overexpressing EGFR. The intravenous administration of the nanoparticles to mice results in the considerable inhibition of tumor growth and the reduction of mortality rates. Pharmacokinetics studies results showed no increase in the aggregation of nanoparticles at the tumor tissue site. The authors concluded the promising potential of this system for enhanced efficacy against lung cancer [ 172 ]. In another report, Patil et al. compared YSA peptide functionalized and nonfunctionalized PLGA nanoparticles to improve delivery to bleomycin treated cultured endothelial cells in a bleomycin induced lung injury mouse model. When human umbilical vein endothelial cells (HUVEC) were treated with bleomycin, the 3 h uptake of both types of nanoparticles was increased up to 2-fold. The results showed that in mice the bleomycin injury led to 2.3 and 4.7 times increases in the lung concentrations of the nonfunctionalized and YSA-functionalized nanoparticles, respectively. The authors stated that PLGA nanoparticle delivery to cultured vascular endothelial cells and mouse lungs in vivo was higher directly after bleomycin treatment, with the delivery likely to be higher for YSA-functionalized nanoparticles [ 173 ]. Single chain technology is a new term developed in nanotechnology in order to broaden the functions of soft nano-objects through chain compaction. Using single chain technology, individual copolymer chains of different natures, compositions and molar masses have been folded intramolecularly to develop single chain nanoparticles (SCNPs). This leads to very small size polymer nanoparticles in the sub-20 nm size [ 174 , 175 ]. The folding is achieved by the self-assembly or crosslinking of functional groups on the precursor polymer, or rather moderated by the external cross-linker. There are several ways to develop SCNPs including dynamic and irreversible covalent crosslinking reactions such as cycloaddition. Moreover, there are huge number of SCNPs that have been introduced, from single and multiblock to star particles, hairpins and tadpole molecules. There are only a few examples present where a functionalized group has been incorporated into SCPNs [ 176 ]. However, these functionalized SCNPs still have not been used for lung cancer targeting. In this context, an insight was given by Benito et al. who evaluated the use of SCPNs based on poly(methacrylic acid) in targeting pancreatic adenocarcinoma. They functionalized SCPNs with somatostatin analogue PTR86 as a targeting moiety since these somatostatin receptors are overexpressed in pancreatic cancer. The imaging results showed a higher accumulation of targeted SCPNs in the tumor compared to the nontargeted nanoparticles, Processes 2021,9, 621 17 of 37 which was due to the enhanced retention in the tissues [ 177 ]. Later, Kröger et al. also reported the greater potential of these types of nanoparticles for cellular targeting [ 178 , 179 ]. Dendrimers are another class of polymers that are constructed by the stepwise addition of layers (generations) of molecules around a central core. This unique physicochemical properties of dendrimers enable a facile utilization of them as templates to funcionalize nanoparticles [ 180 ]. In this regard, a group of researchers reported greater penetration and higher stability of siRNA by implementation of surface-modified poly(propyleneimine) dendrimers. The siRNA nanoparticles were coated by a dithiol bearing cross linker that followed by a layer of PEG. In addition, a synthetic derivative of LHRH was linked at the end of the PEG polymer to conduct siRNA nanoparticles to the cancer cell. The developed system showed timeand concentration-dependent cellular uptake under in vitro conditions. It was proposed by the authors that this approach could be used for the in vivo systemic delivery of siRNA for efficient cancer therapy [181]. Solid lipid nanoparticles or lipid nanoparticles are nanoparticles composed of lipids as a matrix which are exceptionally biodegradable and biocompatible. They possess superior properties such as high drug payload, increased drug stability, large scale production and sterilization [ 182 ]. For instance, in one study Pooja et al. developed and evaluated TF conjugated and etoposide loaded solid lipid nanoparticles. The tissue distribution and pharmacokinetics were studied in Balb/c mice. The nanoparticles showed great anticancer activity of etoposide via antiproliferative assay and induced apoptosis in A549 cells. It was concluded that over expressed TF-receptors showed enhanced efficacy in NSCLC [ 183 ]. Liposomes are similar in design to lipid nanoparticles, but slightly different in composition and function. Riaz et al. developed the TF-7 surface functionalized liposomes loaded with quercetin (QR) for lung cancer therapy. These liposomes were evaluated for cellular uptake and in vitro cytotoxicity study and they exhibited higher cytotoxicity and S-phase cell cycle arrest. The in vivo study showed enhanced liposomes accumulation in the lungs and sustained release up to 96 h [184]. Considering that albumin has remarkable roles in human body, it can be used in the area of medicine and disease treatment. As an example, Yang et al. used hematoporphyrin (HP) functionalized albumin nanoparticles for cancer therapy. These nanoparticles further modified with gamma emitting nuclides ( 99m Tc). HP-albumin nanoparticles showed improved accumulation in A549 and CT-26 cancer cell lines. The evaluation of the pharmacokinetics of 99m Tc chelated HP-albumin nanoparticles via the scintigraphic imaging of rabbits resulted in acceptable imaging properties in the rabbit with a longer biological half-life compared to 99m Tc-HP. The authors concluded these modified albumin nanoparticles could be applied as a diagnostic tool for cancer as well as the obvious application for photodynamic therapy [185]. 9.2. Inorganic Nanoparticles Inorganic nanoparticles including gold, silver, iron oxide and silica nanoparticles have been widely studied as therapeutic agents for cancer treatments in biomedical fields [ 186 ]. Among them, gold nanoparticles are attractive constituents for nanoparticle polymer hybrid materials as they support localized surface plasmon resonances, and the wavelength region of the surface plasmon resonance peak can be adjusted finely through the geometric parameters of the particles [ 187 , 188 ]. In one study, Heo et al. developed the gold nanoparticles surface-functionalized with PEG, biotin and rhodamine B and linked beta-cyclodextrin ( β -CD). The specific interactions of these nanoparticles with cancer cells such as HeLa, A549 and MG63, as well as normal NIH3T3 cells, were evaluated. The authors observed that the modified nanoparticles were more effectively involved with the cancer cells. Confocal laser scanning microscopy (CLSM), fluorescence-activated cell-sorting (FACS) and cell viability analyses showed that the surface functionalized nanoparticles played a significant role in the diagnosis and treatment of the cancer cells, and could be used in theranostic agents [ 189 ]. Guo et al. developed a multifunctional nanocarrier encapsulated with methotrexate via electrostatic interaction between gold nanocluster conjugate chitosan and Processes 2021,9, 621 18 of 37 nucleolin targeting aptamer (AS1411). The in vivo study demonstrated that intravenous administration of nanodrug carrier systems into BALB/c mice caused the accumulation of methotrexate at the tumor site. The results suggested that the developed functionalized system can be applied for an effective delivery for anticancer agents and shows enhanced potential in clinical applications [190]. João Conde et al. fabricated the gold nanoparticles conjugated with siRNA/RGD and studied in a lung cancer murine model. The RGD treatment showed a significant downregulation followed by tumor growth inhibition and the increased survival of the tumor bearing transgenic mice. The results demonstrated that RGD gold nanoparticles stimulate the delivery by intratracheal application in mice that leads to the suppression of tumor cell proliferation. The enhanced targeted delivery of gold nanoparticles encapsulated with siRNA to cancer cells works towards effective silencing of the oncogene. The study showed gold nanoparticles stimulated the inflammatory and immune responses that can promote the therapeutic effect of the siRNA to reduce the tumor size at very low doses [ 191 ]. The schematic illustration of this study is described in Figure 3, which shows the enhanced efficacy of siRNA loaded into functionalized nanoparticles. Processes2021,9,xFORPEERREVIEW18of36   Figure3.InflammatoryresponseandtherapeuticsiRNAsilencingviaRGDnanoparticlesinalungcancermousemodel. Applicationsofsilicaorsilicondioxide(SiO2)asanotherinorganicnanoparticleare broadlyinvestigatedindrugdelivery.Forexample,Munaweeraetal.preparedcisplatin andcisplatin/nitricoxide‐loadedaminefunctionalizedmesoporoussilicananoparticles forthetreatmentoflungcancer.Theresultsdemonstratedthatfornonsmalllungcancer celllines(i.e.,H596andA549),thetoxicityofcisplatin/nitricoxide‐loadedsilicanano‐ particleswashigherthanthatofsilicananoparticlesloadedwithonlycisplatin.Thenitric oxide‐activatedsensitizationofthetumorcelldeath,whichshowedthatnitricoxideisa potentialenhancerofplatinum‐basedlungcancertherapy[192].Anothertypeofinor‐ ganicnanoparticleswithbiomedicalapplicationsiszirconiumoxide(ZrO2).Inonestudy, ZrO2nanoparticleswerecoatedwithaminopropilsilane,tetraoxidecanoicacidoracrylic acid.Thestudiedresultsshoweddose‐dependentsignsofeffectiveness.Itwasconcluded thatsurfacemodificationsoftheZrO2nanoparticleshadverysmalleffectsonthein‐ flammatorylungsofratsandmicebutithadveryclearefficacyintheallergicmouse modelused.Theresultsstatedthattheallergicmicearemoreresponsivetoexposureto surface‐modifiednanoparticles[193].Theuniquepropertiesofmolybdenumdisulfide (MoS2)makeitanattractivecandidatefordrugdeliveryapplications[194].Intheirstudy, WeiZhangetal.developedtheriboflavin5′‐monophosphatesodiumsaltfunctionalized 2DMoS2nanosheetspreparedbythesimpleultrasonicationmethod,thentheyapplied thisnanocompositehavingfineelectrochemicalredoxactivityasaplatformtoimmobi‐ lizeDNAprobe.Theresultsshowedthatthesignaldetectionplatformshowedgreater sensitivitywiththelimitofdetectionof1.2×10−17moll−1forPIK3CAgenefromlungma‐ lignancy.Theconstructedbiosensorwaseasytoachieveandcoulddetectdifferent pathogenicDNAwithoutanintricatelabelprocess[195]. Magneticnanoparticlescanproduceheatunderthemagneticfieldandcanalsode‐ liverdrugstothelungcancersite[196,197].Amongthem,ironoxidenanoparticlesare widelystudiedsystemsforbiomedicalapplications[198,199].Intheirstudy,Huangetal. reportedthesynergyeffectofsuperparamagneticironoxidenanoparticlesalongwithan anticancerdrug(β‐lapachone)forimprovedcancertherapy.Theauthorssuggestedthat combinationofsuperparamagneticironoxidenanoparticleswithreactiveoxygenspe‐ cies‐producingdrugscouldconceivablyenhancedrugefficiency,thuspresentingasyn‐ Figure 3. Inflammatory response and therapeutic siRNA silencing via RGD nanoparticles in a lung cancer mouse model. Applications of silica or silicon dioxide (SiO 2 ) as another inorganic nanoparticle are broadly investigated in drug delivery. For example, Munaweera et al. prepared cisplatin and cisplatin/nitricoxide-loaded amine functionalized mesoporous silica nanoparticles for the treatment of lung cancer. The results demonstrated that for nonsmall lung cancer cell lines (i.e., H596 and A549), the toxicity of cisplatin/nitric oxide-loaded silica nanoparticles was higher than that of silica nanoparticles loaded with only cisplatin. The nitric oxide-activated sensitization of the tumor cell death, which showed that nitric oxide is a potential enhancer of platinum-based lung cancer therapy [ 192 ]. Another type of inorganic nanoparticles with biomedical applications is zirconium oxide (ZrO 2 ). In one study, ZrO 2 nanoparticles were coated with aminopropilsilane, tetraoxidecanoic acid or acrylic acid. The studied results showed dose-dependent signs of effectiveness. It was concluded that surface modifications of the ZrO 2 nanoparticles had very small effects on the inflammatory lungs of rats and mice but it had very clear efficacy in the allergic mouse Processes 2021,9, 621 19 of 37 model used. The results stated that the allergic mice are more responsive to exposure to surface-modified nanoparticles [ 193 ]. The unique properties of molybdenum disulfide (MoS 2 ) make it an attractive candidate for drug delivery applications [ 194 ]. In their study, Wei Zhang et al. developed the riboflavin 5 0 -monophosphate sodium salt functionalized 2D MoS 2 nanosheets prepared by the simple ultrasonication method, then they applied this nanocomposite having fine electrochemical redox activity as a platform to immobilize DNA probe. The results showed that the signal detection platform showed greater sensitivity with the limit of detection of 1.2 × 10 −17 mol L −1 for PIK3CA gene from lung malignancy. The constructed biosensor was easy to achieve and could detect different pathogenic DNA without an intricate label process [195]. Magnetic nanoparticles can produce heat under the magnetic field and can also deliver drugs to the lung cancer site [ 196 , 197 ]. Among them, iron oxide nanoparticles are widely studied systems for biomedical applications [ 198 , 199 ]. In their study, Huang et al. reported the synergy effect of superparamagnetic iron oxide nanoparticles along with an anticancer drug ( β -lapachone) for improved cancer therapy. The authors suggested that combination of superparamagnetic iron oxide nanoparticles with reactive oxygen species-producing drugs could conceivably enhance drug efficiency, thus presenting a synergistic strategy to integrate imaging and therapeutic functions in the discovery of theranostic nanomedicine [ 200 ]. In another study, dextran coated iron oxide nanoparticles were modified with the TAT peptide and they were used to improve the efficiency of the radiation. After performing the internalization study, it was revealed that TAT functionalized nanoparticles enhanced the generation of the reactive oxygen species in comparison to the nanoparticles without any surface modifications. These modified nanoparticles also affected the mitochondrial integrity of A549 cells in combination with the radiation, which resulted in a synergistic decrease in cell viability [201,202]. 9.3. Hybrid Nanoparticles In order to enhance the efficacy of the therapeutic regimen in lung cancer, it is necessary to develop new systems that can increase the survival rates. The development of hybrid nanoparticles (that could comprise both inorganic and organic structural moieties) in conjugation with other genes, biomolecules and other drugs are promising therapeutics systems for efficient targeting [ 203 ]. These types of nanoparticles are important for targeting the tumor site, for its early diagnosis and to measure the risk of malignancy in neighboring cells. These hybrid types are classified into diagnostics, therapeutic and theranostic nanoparticles. Figure 4graphically shows the different types of hybrid nanoparticles that have been applied for lung cancer targeting. In this regard, Sacko et al. studied anticancer effect of a combination therapy of miRNA-29b and genistein loaded in mucin-1 (MUC 1)-aptamer functionalized hybrid nanoparticles in NSCLC A549 cell line. This nanodrug carrier displayed a superior antiproliferative effect compared to individual genistein and miRNA-29b-loaded nanoparticles, thus, it can be considered a potential treatment modality for A549 cell line [ 204 ]. The same research group studied the pharmacokinetic response of novel antineurotensin receptor 1 monoclonal antibody (anti-NTSR1-mAb)-functionalized antimutant K-ras siRNA-loaded hybrid nanoparticles and compared it with that of naked siRNA formulation. As with the main findings, the plasma terminal half-life of the siRNA-loaded nanoparticle-delivered was 11 times higher than that of the naked siRNA formulation. In addition, high performance liquid chromatography (HPLC) analysis showed that the hybrid carrier system could protect the encapsulated siRNA against degradation in systemic circulation. The authors concluded that these hybrid nanoparticles can function as an effective nonviral vector for siRNA delivery for both experimental and clinical uses [205]. Processes 2021,9, 621 20 of 37 Processes2021,9,xFORPEERREVIEW20of36   resveratrolandDTXinbothinvitroandinvivostudies[209].Anotherrelatedstudyre‐ portsthesynthesisandcharacterizationoflipid‐coatedpolyD,L‐lactic‐co‐glycolicacid nanoparticlesthatweremodifiedwithTFtodelivertheDOXintoA549cells.These DOX‐loadedhybridnanoparticlesexhibitedhighercytotoxicityagainstlungcancercells andshowedanimprovedtherapeuticeffectinthelungcancer‐bearingnudemicein comparisontotheirnontargetedcounterparts.Thisfindingmarksthisapproachasan efficienttargeteddrug‐deliverysystemforlungcancertherapy[210].Inanotherstudy, naturallyoccurringchitosanandhyaluronicacidweredepositedonnegativelycharged hybridsolidlipidnanoparticlesthroughlayer‐by‐layer(LbL)assembly.Next,thishybrid systemwasloadedwithDOX/dextransulfatecomplexwiththeaimoftumorspecific targeting.Employingthisapproachunderinvivostudies,theDOXhalf‐lifewasin‐ creasedanditseliminationratewasdecreasedcomparedtothosemeasuredfortheun‐ coatedsolidlipidnanoparticles[211].  Figure 4. Schematic representations of different types of hybrid nanoparticles used for lung cancer targeting (i.e., theranostic hybrid nanoparticles, gene hybrid nanoparticles, combination therapy of hybrid nanoparticles and lipid polymer hybrid nanoparticles). In another study, EGFR-targeted superaparamagnetic iron oxide nanoparticles (SPIONs) were conjugated to carboxy-terminated pluronic F127. The authors investigated the inhalation delivery of these nanoparticles as a potential approach for lung cancer treatment. As in the main findings, EGFR targeting enhanced tumor retention of SPIONs while minimizing systemic exposure. Additionally, magnetic hyperthermia using these nanoparticles resulted in a significant inhibition of in vivo tumor growth [206]. Another type of hybrid delivery system are lipid polymer nanoparticles or core shell lipid polymer nanoparticles, which combine the good biodegradability of polymeric nanoparticles with the excellent biomimetic characteristics of liposomes, and they are Processes 2021,9, 621 21 of 37 effective carrier systems for the delivery of anticancer drugs into the tumor site [ 207 ]. In this context, Bivash Mandal et al. showed that a hybrid system containing biodegradable polycaprolactone (as the core) and phospholipid-shell was able to deliver erlotinib into the lung cancer cells. Performing cell viability studies by this erlotinib-loaded hybrid system, a significant decrease in proliferation of A549 cells was observed, which affords this system a potential application to deliver erlotinib into lung cancer cells [ 208 ]. A similar study was carried out by Song et al. in which they showed the enhanced properties of EGFR-targeted lipid polymer hybrid nanoparticles in the codelivery of resveratrol and DTX. They developed this nanocarrier system by the conjugation of EGF and target the EGFR on the surface of the lung cancer cells in order to increase the endocytosis. Resveratrol (as an antioxidant) improved the production of reactive oxygen species through inducing cytotoxicity. The results exhibited the enhanced antitumor efficacy of resveratrol and DTX in both in vitro and in vivo studies [ 209 ]. Another related study reports the synthesis and characterization of lipid-coated poly D,L-lactic-co-glycolic acid nanoparticles that were modified with TF to deliver the DOX into A549 cells. These DOX-loaded hybrid nanoparticles exhibited higher cytotoxicity against lung cancer cells and showed an improved therapeutic effect in the lung cancer-bearing nude mice in comparison to their nontargeted counterparts. This finding marks this approach as an efficient targeted drug-delivery system for lung cancer therapy [ 210 ]. In another study, naturally occurring chitosan and hyaluronic acid were deposited on negatively charged hybrid solid lipid nanoparticles through layer-by-layer (LbL) assembly. Next, this hybrid system was loaded with DOX/dextran sulfate complex with the aim of tumor specific targeting. Employing this approach under in vivo studies, the DOX half-life was increased and its elimination rate was decreased compared to those measured for the uncoated solid lipid nanoparticles [211]. Another interesting type of nanocarriers in cancer therapy are hydrazine-based pHsensitive nanoparticles. For example, Li et al. designed a dual-ligand lipid based nanoparticle system, in which TF conjugated PEG hydrazone nanoparticles were used for the codelivery of DTX and baicalein into A549 cells. Decorating the lipid nanoparticle with TF could internalize them into the cancer cells. Moreover, this hybrid nanocarrier achieved significant synergistic effects, the best tumor inhibition ability and the lowest systemic toxicity [ 212 ]. A recent progression in lung cancer therapy is gene therapy of lung cancer by applying siRNA hybrid nanoparticles [ 213 ]. Applying hybrid nanoparticles was useful to carefully transport the siRNA into the cytoplasm and cross the limitations of the traditional gene therapy [ 214 ]. For instance, the encapsulation of siRNA in calcium phosphate nanoparticles coated with DOPA (dioleoylphosphatydic acid) could target H460 lung cancer cells [215]. An overview of some other recent studies (that were not mentioned in this section) on developing nanoparticle-based delivery systems as a therapy against lung cancer is presented in Table 3. Table 3. Summary of some recent studies on design of nanoparticle-based delivery approaches for therapy against lung cancer. Nanoparticles Type System Description and the Main Finding Reference Silver NPs 1 (AgNPs) - Poly vinyl pyrrolidone coated AgNPs were used in this study. - After exposure to AgNPs, DNA damage induced by ROS was detected as an increase in bulky DNA adducts by 32P postlabeling and these NPs were suggested as a mediator of ROS-induced genotoxicity. [216] Gold NPs (AuNPs) - Glucose-bound AuNPs combined with radiation, can increase cytotoxicity on A549 cells not only by arresting the G2/M phase, but also by increasing apoptosis. [217] Processes 2021,9, 621 22 of 37 Table 3. Cont. Nanoparticles Type System Description and the Main Finding Reference Quantum dot (QD) - The QD-pulsed dendritic cell vaccine was introduced as a new combination therapy to amplify antitumor immunity. - This combination boosts antigen-specific T-cell immunity and actively inhibits local tumor growth and tumor metastasis in vivo. [218] Liposome - A liposomal curcumin dry powder inhaler for inhalation treatment of primary lung cancer was developed. - This liposomal system showed higher anticancer effects than the other medications regarding pathology and the expression of many cancers. [219] Graphene - Graphene oxide/TiO2/DOX loaded polymer composites were developed in the forms of nanofibers. - In the presence of magnetic field, these nanofibers showed higher proliferation inhibition effect on target lung cancer cells. [220] Carbon nanotubes (CNT) - PEG-coated CNT nanodrugs were designed that improves the mitochondrial targeting of lung cancer cells. - This system increased the anticancer efficacy by increasing mitochondria accumulation rate of cytosol released anticancer nanodrugs. [221] Niosome - A noisome-based formulation containing gemcitabine and cisplatin was presented for lung cancer treatment. - This system reduced cytotoxicity effects against both MRC5 and A549 comparing to with control (gemcitabine and cisplatin alone) after 72 h of treatment. [222] Solid lipid NPs (SLNPs) - Sclareol-loaded SLNPs was formulated and tested for potential geno-cytotoxicity upon A549 lung cancer cells. - Flow cytometry analyses determined early and late apoptosis in sclareol and sclareol-loaded SLNPs treated cells. [223] Hydrogel - A poloxamer-based thermoresponsive hydrogel was developed to exert local tumor control. - This hydrogel demonstrated a dose-dependent cancer cell-specific toxicity in vitro and was retained in situ for at least 14 days in the xenograft model. [224] Iron oxide magnetic NPs - DOX and cetuximab were co-conjugated to dextran-coated Fe3O4 magnetic nanoparticles. - These NPs significantly suppress cell proliferation of A549 cells as compared with A549 cells treated with NPs only conjugated with DOX. [225] Nanoemulsion system - Naringenin nanoemulsions for oral delivery were developed using employing a Box–Behnken design. - These nanoemulsion were more effective than the naringenin solution in reducing Bcl2 expression, while increasing proapoptotic Bax and caspase-3 activity. [226] Processes 2021,9, 621 23 of 37 Table 3. Cont. Nanoparticles Type System Description and the Main Finding Reference Porous Se@SiO2NPs - Porous Se@SiO2NPs were fabricated with antioxidant properties. - These NPs significantly increased the resistance of airway epithelial cells under oxidative injury and shifted lipopolysaccharide-induced gene expression profile closer to the untreated controls. [227] Metal–organic frameworks (MOFs) - A hydrolytically stable mesoporous gadolinium -MOF was prepared. - This nanostructure provided lewis basic sites for 5-Fu delivery and inhibition of human lung cancer cells in vivo and in vitro. [228] 1NPs: Nanoparticles. 9.4. Combinatorial Therapeutic Approach via Hybrid Nanoparticles The encapsulation of different drugs with multiple sites of action is considered to be an efficient method for targeting malignant cells. The application of combinatorial therapeutic approaches will reduce the dose and resistance of the applied anticancer drugs. However, each anticancer drug has a specific biochemical activity; therefore, combined administration would be inappropriate and ineffective in targeting lung cancers. Moreover, combining more drugs can cause harmful effects on healthy organs [ 229 ]. Various hybrid combination therapies have been designed for lung cancer targeting. Multifunctional hybrid nanoparticles have gained more recognition as a combinatorial therapeutic approach. For example, in one study an amphiphilic triblock copolymer functionalized with deoxycholate was synthesized and was used as a nanocarrier to codeliver DOX and PTX into lung cancer cells. Each residue of the copolymeric system comprises a unique property for the complex construction. The codelivery of DOX and PTX using hybrid nanovesicles exhibited an enhanced antitumor effect by reducing the growth of the A549 cells in lung cancer [ 230 ]. Another study demonstrated the enhanced efficacy of dual drug delivery in lung cancer therapy, in which PLGA/methacrylic acid copolymer nanoparticles were developed for the codelivery of DOX and chrysin. This nanoformulation significantly reduced the proliferation of A549 cells. The loaded agents showed higher antitumor activity under the in vitro cell line study [ 231 ]. Based on several studies, it is concluded that the combination therapies using two or more drugs in a single nanoparticle might be more useful for tumor targeting. Hybrid nanoparticle-based combination therapy, including chemotherapy with hyperthermia, can help to reduce the mortality rate in lung cancer patients. Through combining hyperthermia therapy with chemotherapy, upon increasing the temperature of tumor environment up to 40–45 ◦ C, the malignant cells are killed but the healthy cells are not affected [ 232 ]. The hybrid magnetic nanoparticles can be used for combination therapy (chemo and hyperthermia) to achieve better antitumor efficacy. In one study, hydroxyapatite nanoparticles encapsulated with cisplatin were developed to target lung cancer by combining chemotherapy with hyperthermia. The results of this study showed a greater uptake of nanoparticles in A549 cells by activation of the (ERK) signaling pathway [ 233 ]. Figure 5presents a schematic graphic design of combination therapy approaches via different types of nanoparticles. Processes 2021,9, 621 24 of 37 Processes2021,9,xFORPEERREVIEW23of36    Figure5.Schematicrepresentationofcombinationtherapyapproachesintargetinglungcancer.(A)Combinationlipid nanoparticleswithimagingandtherapeuticmoiety(B)Polymerbasednanocapsulehybridtherapywithimagingand targetingmoietyalongwiththerapeuticagent(C)Inorganic‐polymercombinationnanoparticlecoencapsulatedwith drugmolecule,targetingagentandimagingmoiety. 10.SomeClinicalStudiesandMarketedFormulationofNanoparticlesforLungCan‐ cerTreatment Theapplicationofnanoparticle‐baseddrugdeliverysystemsforlungcancertreat‐ mentsisstillinthedevelopmentphase.Nevertheless,therearealreadysomenanoparti‐ cle‐baseddrugsinthemarketandvariousnanobasedtherapeuticsarebeingusedin clinicalstudies.Abraxaneisthefirstnanotechnology‐baseddrugforlungcancertherapy thathaspassedregulatoryscrutinyandisalreadyonthemarketandcanbeusedtotreat breastandpancreaticcanceraswell.Inthisformulation,PTXisbondedtoalbuminna‐ noparticlesasadeliveryvehicle[234].Genexol‐PMisanotherPTX‐loadedformulation, whichisbasedonpolymeric(PEG‐PLA)nanoparticlemicellesandhasbeenapprovedin EuropeandSouthKoreaforthetreatmentofbreastcancerandNSCLC[235,236]. Figure 5. Schematic representation of combination therapy approaches in targeting lung cancer. ( A ) Combination lipid nanoparticles with imaging and therapeutic moiety ( B ) Polymer based nanocapsule hybrid therapy with imaging and targeting moiety along with therapeutic agent ( C ) Inorganic-polymer combination nanoparticle coencapsulated with drug molecule, targeting agent and imaging moiety. 10. Some Clinical Studies and Marketed Formulation of Nanoparticles for Lung Cancer Treatment The application of nanoparticle-based drug delivery systems for lung cancer treatments is still in the development phase. Nevertheless, there are already some nanoparticlebased drugs in the market and various nanobased therapeutics are being used in clinical studies. Abraxane is the first nanotechnology-based drug for lung cancer therapy that has passed regulatory scrutiny and is already on the market and can be used to treat breast and pancreatic cancer as well. In this formulation, PTX is bonded to albumin nanoparticles as a delivery vehicle [ 234 ]. Genexol-PM is another PTX-loaded formulation, which is based on polymeric (PEG-PLA) nanoparticle micelles and has been approved in Europe and South Korea for the treatment of breast cancer and NSCLC [235,236]. Processes 2021,9, 621 25 of 37 In recent years, the US FDA has approbated numerous investigational new drug (IND) applications for nanoformulations, enabling clinical trials for lung cancer. Considering these developments, it seems that nanotechnology could improve the drugs’ effects, overcoming their inherent conventional limits. In Table 4, a list of the FDA approved nanoparticle-based drug delivery systems and a list of INDs being tested in clinical trials are shown [237,238]. Table 4. List of FDA approved and under investigation nanoparticles encapsulated with anticancer drugs. List of FDA Approved Anticancer Drug Loaded Nanoparticles Trade name Generic name Benefits of encapsulation via nanoparticles Reference Doxil (Janssen) Doxorubicin HCl liposome injection Increased delivery to disease site, decreased systemic toxicity of free drug [239,240] Marqibo (Spectrum Pharmaceuticals) Liposomal vincristine Increased delivery to tumor site, decreased systemic toxicity [241] Onivyde (Ipsen Biopharmaceuticals) Liposomal irinotecan Increased delivery to tumor site, decreased systemic toxicity [241] Vyxeos (Jazz Pharmaceuticals) Liposomal daunorubicin and cytarabine Increased efficacy through synergistic delivery of coencapsulated agents [242] List of INDs encapsulated by modified and unmodified nanoparticles under clinical trials Nanoparticle type (Investigation ID) Encapsulated Drug Clinical trial phase Reference Pegylated Liposomal MM-302 DOX Phase 1 [243] HER2-Targeted Liposomes DOX Phase 1 [244] Thermo sensitive Liposome Thermodox (Celsion Corp.) DOX Phase 3 [244] Conjugate Cyclodextran-PEG polymeric nanoparticle CRLX101 Camptothecin phase1 and 2 clinical trials [243] Polymeric nanoparticle Conjugated CRLX301 Docetaxel phase 1 2a[243] Polyglutamic acid-conjugated nanoparticle (poliglumex) Opaxio Paclitaxel Phase3 [239] 11. Conclusions and Future Perspectives In spite of the achieved advances in the drug delivery systems for lung cancer targeting, this cancer type is still the main cause of many deaths in the world. The major problem with the present treatment strategies is a lack of tools and smarter carrier systems for the drug targeting of malignant cells. It is evident from numerous research studies that the surface modification strategy reduces toxicity by changing the half-life, distribution, disposition, stimuli reactivity and therapeutic application. All the applications of surface-modified and hybrid nanoparticles paved the way for the clinical therapeutics through engineered and fine-tuned delivery to the lung tumor while reducing its side effects. These nanomaterials for lung cancer targeting are categorized into diagnostic, therapeutic, and theranostic multifunctional systems. The alteration of the onco-receptor function and modulating their pathways through specific strategies inhibit tumor growth and development through enhanced tumor-specific action. Surface-modified and hybrid nanoparticles can also help to advance the diagnosis process of lung cancer by stepping ahead from anatomical to molecular imaging for more precise diagnosis. However, the chemo-physiological aspects of these carriers should be carefully evaluated for optimal diagnosis. There are several conjugated nanodrugs recently filed in the list of the FDA’s new drug applications. 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