A REVIEW OF NANOPARTICLE-BASED STRATEGIES FOR OVERCOMING THE BLOOD-BRAIN BARRIER IN NEURODEGENERATIVE DISEASE THERAPY
Abstract
Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and related disorders, remain difficult to treat effectively due to the restrictive nature of the blood–brain barrier, which severely limits drug delivery to the central nervous system. Many therapeutic agents with proven molecular efficacy fail to achieve clinical success because they cannot reach target sites in the brain at sufficient concentrations. This review aims to critically analyze nanoparticle-based strategies developed to overcome the blood–brain barrier and to evaluate their potential in neurodegenerative disease therapy. A narrative-integrative review method was employed, drawing on peer-reviewed articles indexed in major scientific databases, including studies on lipid-based, polymeric, inorganic, and biomimetic nanoparticles. The reviewed evidence indicates that nanoparticle systems significantly enhance brain delivery through mechanisms such as receptor-mediated transcytosis, adsorption-mediated transport, and biomimicry, leading to improved pharmacokinetics and therapeutic efficacy in preclinical models. Lipid-based and biomimetic nanoparticles demonstrate the greatest translational promise due to favorable safety and biological compatibility, while polymeric systems offer high design flexibility. Despite these advances, challenges related to long-term safety, reproducibility, and clinical translation persist. In conclusion, nanoparticle-based delivery represents a pivotal strategy for overcoming the blood–brain barrier, and continued interdisciplinary research is essential to translate these technologies into effective therapies for neurodegenerative diseases.
Keywords: blood–brain barrier; nanoparticles; neurodegenerative diseases; nanomedicine; targeted drug delivery
Full text article
References
Alsafiah, C. M., Tabroni, I., Mark, E., & Maharjan, K. (n.d.). Development of Labyrinth Media to Stimulate Prosocial Behavior Skills of 5-6 years old Children in Purwakarta. Biomedical and Techno Nanomaterials, 1(1), 62–72. https://doi.org/10.55849/jsca.v1i1.453
Arellano, A., Palma-Florez, S., Cabrera, P., Cortés-Adasme, E., Bolaños, K., Celis, F., Araya-Vergara, A. J., Pérez, M., Crespo, A., Matus, M. H., Araya, E., Aldunate, R., Kogan, M. J., Samitier, J., Lagunas, A., Mir, M., & Hassan, N. (2025). Attenuation of blood-brain barrier dysfunction by functionalized gold nanoparticles against amyloid-? peptide in an Alzheimer’s disease-on-a-chip model. Materials Today Bio, 35, 102453. https://doi.org/10.1016/j.mtbio.2025.102453
Arman, S. A., Wang, Y., & Zou, G. (2023). Threeyasa Group Banyuwangi Company Profile Design. Biomedical and Techno Nanomaterials, 1(1), 14–24. https://doi.org/10.55849/jsca.v1i1.404
Bhati, V., Prasad, S., & Kabra, A. (2025). RNA-based therapies for neurodegenerative disease: Targeting molecular mechanisms for disease modification. Molecular and Cellular Neuroscience, 133, 104010. https://doi.org/10.1016/j.mcn.2025.104010
Chen, Y., Sun, X., Xi, Y., Luo, Z., Lai, H., Zhu, D., Zhang, Y., Xu, F., Li, J., Zhou, J., Ding, Y., & Zhang, H. (2025). Pathology-directed drug delivery strategies: How to overcome blood–brain barrier for the treatment of brain diseases. Acta Pharmaceutica Sinica B. https://doi.org/10.1016/j.apsb.2025.10.016
Dargude, S., Chabukswar, A., & Jagdale, S. (2025). Breaking the brain barrier: Hybrid nanoparticle-enabled delivery for next-gen neurotherapeutics. Hybrid Advances, 11, 100513. https://doi.org/10.1016/j.hybadv.2025.100513
Gokce, C., Altun, B., Kirit, E., Yavuz, H., Uyar, R., Celik, D., & Yilmazer, A. (2025). Unlocking the human blood-brain barrier (BBB) characteristics for the development of nano-delivery strategies for central nervous system therapies. Journal of Drug Delivery Science and Technology, 108, 106961. https://doi.org/10.1016/j.jddst.2025.106961
Hasanah, I. U., Tabroni, I., Brunel, B., & Alan, M. (2023). Development of Media Matching Box to stimulate symbolic thinking skills in children aged 4-5 years. Biomedical and Techno Nanomaterials, 1(1), 1–13. https://doi.org/10.55849/jsca.v1i1.442
Ibrahim, R. M., Teaima, M., El-Nabarawi, M., & Badawi, N. M. (2024). Intranasal delivery of chitosan-based nanoparticles as an innovative way for management of neurodegenerative disorders: A comprehensive review of advanced strategies for CNS targeting. Journal of Drug Delivery Science and Technology, 99, 105885. https://doi.org/10.1016/j.jddst.2024.105885
Inamdar, A., Gurupadayya, B., Halagali, P., S., N., Pathak, R., Singh, H., & Sharma, H. (2025). Cutting-edge Strategies for Overcoming Therapeutic Barriers in Alzheimer’s Disease. Current Pharmaceutical Design, 31(8), 598–618. https://doi.org/10.2174/0113816128344571241018154506
Inamdar, A., Gurupadayya, B., Halagali, P., Tippavajhala, V. K., Khan, F., Pathak, R., & Sharma, H. (2025). Unraveling Neurological Drug Delivery: Polymeric Nanocarriers for Enhanced Blood-Brain Barrier Penetration. Current Drug Targets, 26(4), 243–266. https://doi.org/10.2174/0113894501339455241101065040
Jia, Y., Wu, Y., Zhang, F., Sun, Y., & Liu, Y. (2025). Overcoming the blood–brain barrier challenge: Nanotechnology-enhanced photodynamic therapy for glioblastoma treatment. Chemical Communications, 61(67), 12431–12448. https://doi.org/10.1039/d5cc03192c
Khazeni, S., & Mousavi, S. Y. (2025). Crossing the blood-brain barrier: The therapeutic potential of lncRNAs in neurosurgery. European Journal of Surgical Oncology, 51(12), 110487. https://doi.org/10.1016/j.ejso.2025.110487
Kong, X., Hu, B., Luo, X., Zhou, J., Zhang, C., Zi, R., Zhang, C., Zhang, Y., Jiang, H., Liu, T., Zhang, Y., Dong, Y., Zhao, X., & Hu, J. (2025). TfR-aptamer programmed DNA nanoflowers penetrate the blood-brain barrier for synergistic NLRP3 silencing and neuroinflammation therapy. Chemical Engineering Journal, 526, 170771. https://doi.org/10.1016/j.cej.2025.170771
Liao, J., He, W., Li, L., Wang, J., Gong, L., Zhang, Q., & Lin, Z. (2025). Mitochondria in brain diseases: Bridging structural-mechanistic insights into precision-targeted therapies. Cell Biomaterials, 1(2), 100016. https://doi.org/10.1016/j.celbio.2025.100016
Luo, Q., Yang, J., Yang, M., Wang, Y., Liu, Y., Liu, J., Kalvakolanu, D. V., Cong, X., Zhang, J., Zhang, L., Guo, B., & Duo, Y. (2025). Utilization of nanotechnology to surmount the blood-brain barrier in disorders of the central nervous system. Materials Today Bio, 31, 101457. https://doi.org/10.1016/j.mtbio.2025.101457
Mahakalakar, N., Mohariya, G., Taksande, B., Kotagale, N., Umekar, M., & Vinchurney, M. (2025). “Nattokinase as a potential therapeutic agent for preventing blood-brain barrier dysfunction in neurodegenerative disorders.” Brain Research, 1849, 149352. https://doi.org/10.1016/j.brainres.2024.149352
Mahdi, E., Alalikhan, A., Ridha-Salman, H., Azeez Ameen, M., Hannon Abbass, Z., Bemidinezhad, A., & Soukhtanloo, M. (2025). Perfluorocarbon nanotechnologies for blood-brain barrier modulation: Enhancing drug delivery and neuroprotection. Biochemical and Biophysical Research Communications, 789, 152843. https://doi.org/10.1016/j.bbrc.2025.152843
Mishra, K., Tripathi, S., Tiwari, A. K., Rana, R., Yadav, P., & Chourasia, M. K. (2025). Cerium-based nanoparticles for neurodegeneration: Emerging redox therapeutics beyond pharmaceuticals. RSC Advances, 15(45), 37540–37569. https://doi.org/10.1039/d5ra03599f
Naghib, S. M., Khorasani, M. A., Sharifianjazi, F., & Tavamaishvili, K. (2025). Bifunctional chitosan-based nanocarriers as promising therapeutic approach for brain disease therapy: A critical review focusing on multiple sclerosis over emerging strategies, technologies and applications. International Journal of Biological Macromolecules, 330, 148003. https://doi.org/10.1016/j.ijbiomac.2025.148003
Naimi, N., Seyedmirzaei, H., Hassannejad, Z., & Soltani Khaboushan, A. (2024). Advanced nanoparticle strategies for optimizing RNA therapeutic delivery in neurodegenerative disorders. Biomedicine & Pharmacotherapy, 175, 116691. https://doi.org/10.1016/j.biopha.2024.116691
Narayan, S., Gupta, P. K., & Nagpal, K. (2025). Revolutionizing Neurological Therapies: The Multifaceted Potential of Zein-Based Nanoparticles for Brain-Targeted Drug Delivery. Molecular Pharmaceutics, 22(7), 3803–3823. https://doi.org/10.1021/acs.molpharmaceut.5c00062
Nopiyanti, H., Tabroni, I., Barroso, U., & Intes, A. (2023). Product Development of Unique Clothing Learning Media to Stimulate Fine Motor Skills of 4-5 Years Old Children. Biomedical and Techno Nanomaterials, 1(1), 48–61. https://doi.org/10.55849/jsca.v1i1.452
Parvar, S. J., Wong, C. I., Lewis, A., Szychot, E., Morris, C. J., Shorthouse, D., & Dziemidowicz, K. (2025). Convection-enhanced delivery for brain malignancies: Technical parameters, formulation strategies and clinical perspectives. Advanced Drug Delivery Reviews, 224, 115657. https://doi.org/10.1016/j.addr.2025.115657
Pedder, J. H., Sonabend, A. M., Cearns, M. D., Michael, B. D., Zakaria, R., Heimberger, A. B., Jenkinson, M. D., & Dickens, D. (2025). Crossing the blood–brain barrier: Emerging therapeutic strategies for neurological disease. The Lancet Neurology, 24(3), 246–260. https://doi.org/10.1016/S1474-4422(24)00476-9
Pineiro-Alonso, L., Rubio-Prego, I., Lobyntseva, A., González-Freire, E., Langer, R., & Alonso, M. J. (2025). Nanomedicine for targeting brain Neurodegeneration: Critical barriers and circadian rhythm Considerations. Advanced Drug Delivery Reviews, 222, 115606. https://doi.org/10.1016/j.addr.2025.115606
Pramoda, G., Verma, R. K., Kesharwani, P., & Shukla, R. (2025). Surface-functionalized nanoparticles for targeted drug delivery across the blood-brain barrier: Advances and challenges in neurodegenerative disease therapy. Journal of Molecular Liquids, 433, 127938. https://doi.org/10.1016/j.molliq.2025.127938
Rafati, N., Zarepour, A., Bigham, A., Khosravi, A., Naderi-Manesh, H., Iravani, S., & Zarrabi, A. (2024). Nanosystems for targeted drug Delivery: Innovations and challenges in overcoming the Blood-Brain barrier for neurodegenerative disease and cancer therapy. International Journal of Pharmaceutics, 666, 124800. https://doi.org/10.1016/j.ijpharm.2024.124800
Rawat, E., Sharma, S., Vyas, S., Alsaidan, O. A., Kapoor, D. U., & Prajapati, B. G. (2025). Advances in alginate-based nanoformulations: Innovative and effective strategies for targeting and treating brain disorders. International Journal of Pharmaceutics, 681, 125851. https://doi.org/10.1016/j.ijpharm.2025.125851
Romero-Ben, E., Goswami, U., Soto-Cruz, J., Mansoori-Kermani, A., Mishra, D., Martin-Saldaña, S., Muñoz-Ugartemendia, J., Sosnik, A., Calderón, M., Beloqui, A., & Larrañaga, A. (2025). Polymer-based nanocarriers to transport therapeutic biomacromolecules across the blood-brain barrier. Acta Biomaterialia, 196, 17–49. https://doi.org/10.1016/j.actbio.2025.02.065
Rosales, T. K. O., Silva, P. B. V. da, Oliveira, P. A., Zanetti, M. V., Santos, H. A., & Fabi, J. P. (2025). Nanoencapsulated flavonoids for enhanced modulation of the microbiota-gut-brain axis and neurodegenerative add-on therapy. Trends in Food Science & Technology, 164, 105264. https://doi.org/10.1016/j.tifs.2025.105264
Sadat Razavi, Z., Sina Alizadeh, S., Sadat Razavi, F., Souri, M., & Soltani, M. (2025). Advancing neurological disorders therapies: Organic nanoparticles as a key to blood-brain barrier penetration. International Journal of Pharmaceutics, 670, 125186. https://doi.org/10.1016/j.ijpharm.2025.125186
Sandhu, J. K., Thakur, K., Cai, D., Péladeau, C. L., Hewitt, M., & Ghadban, W. (2025). Chapter 18—The path towards precision medicine: Next generation biotherapeutics and delivery strategies across the blood–brain barrier for the treatment of neurodegenerative diseases. In R. C. Sobti, D. W. Wilson, H. S. Buttar, I. G. Télessy, & A. Sobti (Eds.), Molecular Medicine and Biomedical Research in the Era of Precision Medicine (pp. 353–395). Academic Press. https://doi.org/10.1016/B978-0-443-22300-6.00055-3
Sharma, R., Monika, Tyagi, B., Gupta, D., Mazumder, R., & Mazumder, A. (2025). To Explore Nasal-Brain Lymphatic System for Brain-Targeted Drug Delivery and to Treat Neurodegenerative Diseases. Central Nervous System Agents in Medicinal Chemistry, 25(4), 437–453. https://doi.org/10.2174/0118715249329586240924105624
Teresia, V., Jie, L., & Jixiong, C. (202 C.E.). Interactive Learning Media Application For The Introduction Of Human Needs In Children Aged. Biomedical and Techno Nanomaterials, 1(1), 25–36. https://doi.org/10.55849/jsca.v1i1.406
Thakur, N., Kumar, T., Singh, C., Kumar, R., & Kumar, A. (2025). Cell membrane-coated nanoparticles for neurodegenerative disorders management. International Journal of Pharmaceutics, 681, 125875. https://doi.org/10.1016/j.ijpharm.2025.125875
Vargas, R., Lizano-Barrantes, C., Romero, M., Valencia-Clua, K., Narváez-Narváez, D. A., Suñé-Negre, J. M., Pérez-Lozano, P., García-Montoya, E., Martinez-Martinez, N., Hernández-Munain, C., Suñé, C., & Suñé-Pou, M. (2024). The piper at the gates of brain: A systematic review of surface modification strategies on lipid nanoparticles to overcome the Blood-Brain-Barrier. International Journal of Pharmaceutics, 665, 124686. https://doi.org/10.1016/j.ijpharm.2024.124686
Authors
Copyright (c) 2025 Thika Marliana, Bina Magar, Samuel Denis

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.