1 The immunological implications of nanocomposite drug delivery systems 1 This review discusses recent advances in nanocomposite applications, with a particular concentrate on their progress as drug delivery systems. It explores the intrinsic properties of nanocomposites that effect their interaction with the immune system and potential in vivo toxicity. It also includes the immune system's interaction with nanomaterials, immunological responses provoked by nanocomposite systems, and the factors that impact immune reactions such as size, shape, surface properties, composition, and biodegradability. The review also discusses surface modifications and targeting ligands that can optimize nanocomposite performance. Through understanding nano-bio interfaces technology, researchers can design bio-effective nanomaterials that open new possibilities for biomedical applications, especially as targeted and safe drug delivery platforms 1 7 Mehrasa Nikandish King’s College LondonFaculty of Life Science and Medicine King’s College London, London UK mehrasa.1.nikandish@kcl.ac.uk Bahram Rezazadeh Moghaddam School of Health Sciences, University of Georgia,Tbilisi Georgia Bahram.std@ug.edu.ge Melika Chinaveh School of Science and Health, The University of Georgia, Tbilisi Georgia chinavehmelika@gmail.com Aynaz Ziaeijazi School of Allied Medical Sciences, Isfahan University of Medical Sciences, Isfahan Iran aynazziyaee2005@gmail.com Leila Akhvlediani School of Medicine and Health Sciences, BAU International University Batumi, 6010 Batumi Georiga leila.akhvlediani@bauinternational.edu.ge Ana Gujabidze Pharmaceutical Company LTD Davati, Chief Microbiology, Tbilisi, Georgia University of Georgia, Invited Lecturer in Biochemistry and Microbiology, Tbilisi Georiga Ana174g@gmail.com Controlled release Drug delivery systems Nanocomposites Immunology Targeted drug delivery [1] A. Tariq, S.A. Bhawani, M. Nisar, M.R. Asaruddin, K.M. Alotaibi, Starch-based nanocomposites for gene delivery, Polysaccharide-based nanocomposites for gene delivery and tissue engineering, Woodhead Publishing, (2021) 263.##[2] T.E. Twardowski, Introduction to nanocomposite materials: properties, processing, characterization, DEStech Publications, Inc2007.##[3] A. Yusuf, A.R.Z. Almotairy, H. Henidi, O.Y. Alshehri, M.S. Aldughaim, Nanoparticles as drug delivery systems: a review of the implication of nanoparticles’ physicochemical properties on responses in biological systems, Polymers 15(7) (2023) 1596.##[4] G. Armstrong, An introduction to polymer nanocomposites, European Journal of Physics 36(6) (2015) 063001.##[5] N.H. Al-Mutairi, A.H. Mehdi, B.J. Kadhim, Nanocomposites materials definitions, types and some of their applications: A review, European Journal of Research Development and Sustainability 3(2) (2022) 102-108.##[6] M. Hao, B. Chen, X. Zhao, N. Zhao, F.-J. Xu, Organic/inorganic nanocomposites for cancer immunotherapy, Materials Chemistry Frontiers 4(9) (2020) 2571-2609.##[7] M. Sheikhpour, L. Barani, A. Kasaeian, Biomimetics in drug delivery systems: A critical review, Journal of Controlled Release 253 (2017) 97-109.##[8] J. Njuguna, F. Ansari, S. Sachse, V.M. Rodriguez, S. Siqqique, H. Zhu, Nanomaterials, nanofillers, and nanocomposites: types and properties, Health and environmental safety of nanomaterials, Elsevier2021, pp. 3-37.##[9] J. Requejo-Isidro, R. Del Coso, J. Solis, J. Gonzalo, C.N. Afonso, Role of surface-to-volume ratio of metal nanoparticles in optical properties of Cu: Al2O3 nanocomposite films, Applied physics letters 86(19) (2005).##[10] M. Shahbaz, H. Naeem, S. Murtaza, N. Ul-Huda, M. Tayyab, A. Hamza, U. Momal, Application of starch as an active ingredient for the fabrication of nanocomposite in food packaging, Starch Based Nanomaterials for Food Packaging, Elsevier2024, pp. 161-208.##[11] M.D. Malyshev, D.V. Guseva, V.V. Vasilevskaya, P.V. Komarov, Effect of Nanoparticles Surface Bonding and Aspect Ratio on Mechanical Properties of Highly Cross-Linked Epoxy Nanocomposites: Mesoscopic Simulations, Materials 14(21) (2021) 6637.##[12] C.C. Okpala, The benefits and applications of nanocomposites, Int. J. Adv. Eng. Tech 12 (2014) 18.##[13] W.S. Khan, N.N. Hamadneh, W.A. Khan, Polymer nanocomposites–synthesis techniques, classification and properties, Science and applications of Tailored Nanostructures 50 (2016).##[14] V. Kodolov, V. Trineeva, Fundamental definitions for domain of nanostructures and metal/carbon nanocomposites, Nanostructure, Nanosystems and Nanostructured Materials: Theory, Production and Development (2013) 1-42.##[15] L. Chen, Classification of Nanofillers, Nano‐Objects, Nanomaterials, and Polymer Nanocomposites Based on Chemical Nature and Identity, Chemical Physics of Polymer Nanocomposites: Processing, Morphology, Structure, Thermodynamics, Rheology 1 (2024) 1-14.##[16] C.C. Okpala, Nanocomposites–an overview, Int. J. Eng. Res. Dev 8(11) (2013) 17.##[17] P.I. Dolez, Nanomaterials definitions, classifications, and applications, Nanoengineering, Elsevier2015, pp. 3-40.##[18] P. Sharma, N.-Y. Jang, J.-W. Lee, B.C. Park, Y.K. Kim, N.-H. Cho, Application of ZnO-based nanocomposites for vaccines and cancer immunotherapy, Pharmaceutics 11(10) (2019) 493.##[19] K.K. Jain, An overview of drug delivery systems, Drug delivery systems (2019) 1-54.##[20] A.C. Anselmo, S. Mitragotri, An overview of clinical and commercial impact of drug delivery systems, Journal of Controlled Release 190 (2014) 15-28.##[21] A.C. Berkowitz, D.M. Goddard, Novel drug delivery systems: future directions, Journal of Neuroscience Nursing 41(2) (2009) 115-120.##[22] A. Sultana, M. Zare, V. Thomas, T.S. Kumar, S. Ramakrishna, Nano-based drug delivery systems: Conventional drug delivery routes, recent developments and future prospects, Medicine in Drug Discovery 15 (2022) 100134.##[23] O. Kayser, A. Lemke, N. Hernandez-Trejo, The impact of nanobiotechnology on the development of new drug delivery systems, Current pharmaceutical biotechnology 6(1) (2005) 3-5.##[24] M.S. Alam, A. Akhtar, I. Ahsan, S. Shafiq-un-Nabi, Pharmaceutical product development exploiting 3D printing technology: conventional to novel drug delivery system, Current pharmaceutical design 24(42) (2018) 5029-5038.##[25] V. Andretto, A. Rosso, S. Briançon, G. Lollo, Nanocomposite systems for precise oral delivery of drugs and biologics, Drug delivery and translational research 11 (2021) 445-470.##[26] G.C. Lôbo, K.L. Paiva, A.L.G. Silva, M.M. Simões, M.A. Radicchi, S.N. Báo, Nanocarriers used in drug delivery to enhance immune system in cancer therapy, Pharmaceutics 13(8) (2021) 1167.##[27] A.U. Kura, M.Z. Hussein, S. Fakurazi, P. Arulselvan, Layered double hydroxide nanocomposite for drug delivery systems; bio-distribution, toxicity and drug activity enhancement, Chemistry Central Journal 8(1) (2014) 47.##[28] M. Jafarbeglou, M. Abdouss, A.M. Shoushtari, M. Jafarbeglou, Clay nanocomposites as engineered drug delivery systems, RSC advances 6(55) (2016) 50002-50016.##[29] J.M. Kim, D.H. Kim, H.J. Park, H.W. Ma, I.S. Park, M. Son, S.Y. Ro, S. Hong, H.K. Han, S.J. Lim, Nanocomposites-based targeted oral drug delivery systems with infliximab in a murine colitis model, Journal of nanobiotechnology 18 (2020) 1-13.##[30] S. Salatin, J. Barar, M. Barzegar-Jalali, K. Adibkia, M.A. Milani, M. Jelvehgari, Hydrogel nanoparticles and nanocomposites for nasal drug/vaccine delivery, Archives of pharmacal research 39 (2016) 1181-1192.##[31] U. Chintapula, S.-U. Karim, P.R. Iyer, H. Asokan-Sheeja, B. Neupane, F. Nazneen, H. Dong, F. Bai, K.T. Nguyen, A novel nanocomposite drug delivery system for SARS-CoV-2 infections, Nanoscale Advances 6(15) (2024) 3747-3758.##[32] D. Simberg, Iron oxide nanoparticles and the mechanisms of immune recognition of nanomedicines, Taylor and Francis, 2016, pp. 741-743.##[33] S. Hussain, J.A. Vanoirbeek, P.H. Hoet, Interactions of nanomaterials with the immune system, Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 4(2) (2012) 169-183.##[34] A.A. Aljabali, M.A. Obeid, R.M. Bashatwah, Á. Serrano-Aroca, V. Mishra, Y. Mishra, M. El-Tanani, A. Hromić-Jahjefendić, D.N. Kapoor, R. Goyal, Nanomaterials and their impact on the immune system, International journal of molecular sciences 24(3) (2023) 2008.##[35] B. Fadeel, Hide and seek: nanomaterial interactions with the immune system, Frontiers in immunology 10 (2019) 133.##[36] S. Yan, W. Gu, Z.P. Xu, Re-considering how particle size and other properties of antigen–adjuvant complexes impact on the immune responses, Journal of colloid and interface science 395 (2013) 1-10.##[37] J.M. Silva, M. Videira, R. Gaspar, V. Préat, H.F. Florindo, Immune system targeting by biodegradable nanoparticles for cancer vaccines, Journal of controlled release 168(2) (2013) 179-199.##[38] E. Vega, J.M. Burgos, E.B. Souto, M.L. García, M. Pujol, E. Sánchez-López, Biodegradable nanoplatforms for antigen delivery: part I–state of the art review of polymeric nanoparticles for cancer immunotherapy, Expert Opinion on Drug Delivery 21(8) (2024) 1251-1262.##[39] J.W. Grunberger, M.A. Dobrovolskaia, H. Ghandehari, Immunological properties of silica nanoparticles: a structure–activity relationship study, Nanotoxicology 18(6) (2024) 542-564.##[40] A. Petrizzo, C. Conte, M. Tagliamonte, M. Napolitano, K. Bifulco, V. Carriero, A. De Stradis, M. Tornesello, F. Buonaguro, F. Quaglia, Functional characterization of biodegradable nanoparticles as antigen delivery system, Journal of Experimental and Clinical Cancer Research 34 (2015) 1-13.##[41] N. Beniwal, A. Verma, C.L. Putta, A.K. Rengan, Recent trends in bio-nanomaterials and non-invasive combinatorial approaches of photothermal therapy against cancer, Nanotheranostics 8(2) (2024) 219.##[42] X. Yu, Q. Zhang, L. Wang, Y. Zhang, L. Zhu, Engineered nanoparticles for imaging and targeted drug delivery in hepatocellular carcinoma, Experimental Hematology and Oncology 14(1) (2025) 62.##[43] E. Marin, M.I. Briceño, C. Caballero-George, Critical evaluation of biodegradable polymers used in nanodrugs, International journal of nanomedicine (2013) 3071-3091.##[44] T. Akagi, M. Baba, M. Akashi, Biodegradable nanoparticles as vaccine adjuvants and delivery systems: regulation of immune responses by nanoparticle-based vaccine, Polymers in nanomedicine (2012) 31-64.##[45] G. Herrera, S. Paudel, S. Lupini, C. Astete, C. Sabliov, D. Rodrigues, Biodegradable nanoparticles aid the gut microbial community in delaying antibiotic resistance emergence, Environmental Science: Nano 11(11) (2024) 4501-4512.##[46] S.A. Arabiyat, Prospectus and Concerns of Immunomodulatory Nanotechnologies and Nanoparticles Biocompatibility and Toxicity, Nanotechnology Based Microbicides and Immune Stimulators, Springer2025, pp. 165-189.##[47] J.M. Burgos, E. Vega, M.L. García, M. Pujol, E. Sánchez-López, E.B. Souto, Biodegradable nanoplatforms for antigen delivery: part II–nanoparticles, hydrogels, and microneedles for cancer immunotherapy, Expert Opinion on Drug Delivery 21(9) (2024) 1385-1394.##[48] A. Pisani, G. Bardi, Immunology of biodegradable nanoparticles: A brief overview on a wide growing field, Exploration of Immunology 1(1) (2021) 48-60.##[49] N. Ying, X. Lin, M. Xie, D. Zeng, Effect of surface ligand modification on the properties of anti-tumor nanocarrier, Colloids and Surfaces B: Biointerfaces 220 (2022) 112944.##[50] A. Abdelkawi, A. Slim, Z. Zinoune, Y. Pathak, Surface Modification of Metallic Nanoparticles for Targeting Drugs, Coatings 13(9) (2023) 1660.##[51] P. Huang, C. Wang, H. Deng, Y. Zhou, X. Chen, Surface engineering of nanoparticles toward cancer theranostics, Accounts of Chemical Research 56(13) (2023) 1766-1779.##[52] T. Thomsen, H.-A. Klok, Chemical cell surface modification and analysis of nanoparticle-modified living cells, ACS applied bio materials 4(3) (2021) 2293-2306.##[53] F. Sabir, M. Qindeel, M. Zeeshan, Q. Ul Ain, A. Rahdar, M. Barani, E. González, M.A. Aboudzadeh, Onco-Receptors Targeting in Lung Cancer via Application of Surface-Modified and Hybrid Nanoparticles: A Cross-Disciplinary Review, Processes 9(4) (2021) 621.##[54] D.F. Moyano, Y. Liu, D. Peer, V.M. Rotello, Modulation of immune response using engineered nanoparticle surfaces, Small 12(1) (2016) 76-82.##[55] G. Moku, V.R. Gopalsamuthiram, T.R. Hoye, J. Panyam, Surface modification of nanoparticles: methods and applications, Surface modification of polymers: Methods and applications (2019) 317-346.##[56] S.M. Honmane, M.S. Charde, S.S. Salunkhe, P.B. Choudhari, S.N. Nangare, Polydopamine surface-modified nanocarriers for improved anticancer activity: Current progress and future prospects, OpenNano 7 (2022) 100059.##[57] N.H. Abd Ellah, S.A. Abouelmagd, Surface functionalization of polymeric nanoparticles for tumor drug delivery: approaches and challenges, Expert opinion on drug delivery 14(2) (2017) 201-214.##[58] Y. Choi, B.K. Cho, S.H. Seok, C. Kim, J.H. Ryu, I.C. Kwon, Controlled spatial characteristics of ligands on nanoparticles: determinant of cellular functions, Journal of Controlled Release 360 (2023) 672-686.##[59] A. Bandyopadhyay, R.L. Fine, S. Demento, L.K. Bockenstedt, T.M. Fahmy, The impact of nanoparticle ligand density on dendritic-cell targeted vaccines, Biomaterials 32(11) (2011) 3094-3105.##[60] A. Fakhari, A. Baoum, T.J. Siahaan, K.B. Le, C. Berkland, Controlling ligand surface density optimizes nanoparticle binding to ICAM-1, Journal of pharmaceutical sciences 100(3) (2011) 1045-1056.##[61] Z. Luo, Z. Yi, X. Liu, Surface engineering of lanthanide nanoparticles for oncotherapy, Accounts of Chemical Research 56(4) (2023) 425-439.