Volume 10 Number 2 2026
Engineered Extracellular Vesicles Escape Endosomal Trapping to Deliver Alzheimer's Therapeutics Across the Blood-Brain Barrier
Hashim Abdul-Sattar J. Al-Bajalani 1* Md Sohel Rana 2, Yoghinni Manogaran 3, Ahmed Ahmed Al-Akwaa 4
Integrative Biomedical Research 10 (2) 1-8 https://doi.org/10.25163/biomedical.10210944
Submitted: 27 August 2026 Revised: 18 October 2026 Accepted: 27 October 2026 Published: 29 October 2026
Alzheimer’s disease (AD) remains one of the most stubborn problems in modern medicine, not for lack of promising molecules but because so few of them ever reach the brain in usable form. The blood–brain barrier turns away almost every large-molecule therapeutic, and even when a nanocarrier does get across, it tends to become trapped inside endosomes before its cargo can do any good. This review takes a close look at extracellular vesicles (EVs) as a possible way around both problems. We trace how naïve exosomes and microvesicles arise, what they naturally carry, and why their biocompatibility makes them attractive starting points for brain-targeted delivery—before turning to the harder question of how they can be engineered to actually work as drugs. Three broad engineering strategies are examined: post-isolation surface decoration with endosomolytic peptides, genetic modification of producer cells to install viral or human fusogens, and biophysical remodeling of the lipid bilayer itself. Each offers a different route past the endosomal bottleneck, and each carries its own trade-offs in immunogenicity, manufacturing complexity, and regulatory burden. We then synthesize preclinical and early clinical evidence, including a Phase I/II trial of intranasal mesenchymal stem cell–derived EVs, to gauge how close these platforms are to genuine clinical use. Across the literature, a consistent picture emerges: engineered EVs can achieve striking gains in endosomal escape and target-cell specificity in animal models, yet scalable, GMP-compliant, MISEV-aligned manufacturing remains the binding constraint on translation. We conclude by outlining what still needs to happen—standardized potency assays, dual-engineering platforms combining targeting and escape modules, and harmonized regulatory pathways—before EV nanomedicine can meaningfully change how Alzheimer’s disease is treated.
Keywords: extracellular vesicles; exosomes; Alzheimer’s disease; blood–brain barrier; endosomal escape; drug delivery; bioengineering; nanomedicine
Akishiba, M., Takeuchi, T., Kawaguchi, Y., Sakamoto, K., Yu, H. H., Nakase, I., Takatani-Nakase, T., Madani, F., Gräslund, A., & Futaki, S. (2017). Cytosolic antibody delivery by lipid-sensitive endosomolytic peptide. Nature Chemistry, 9(8), 751–761. https://doi.org/10.1038/nchem.2779
Allevi, D., Luchicchi, A., & Orefice, N. S. (2025). Nanocarrier-based drug delivery for mild cognitive impairment: Extracellular vesicles and carbon nanotubes as emerging therapeutic tools. Biomedicine & Pharmacotherapy, 190, 118381. https://doi.org/10.1016/j.biopha.2025.118381
Ayupova, A. I., Sidorova, A. S., Luzina, E. A., Sufianov, A. A., Sufianova, G. Z., Zaynutdinov, A. M., Rizvanov, A. A., & Solovyeva, V. V. (2026). Application of mesenchymal stromal cells and their exosomes in neurodegenerative diseases and lysosomal storage diseases. Cells, 15(16), 1540. https://doi.org/10.3390/cells15161540
Bonsergent, E., Grisard, E., Buchrieser, J., Schwartz, O., Théry, C., & Lavieu, G. (2021). Quantitative characterization of extracellular vesicle uptake and content delivery within mammalian cells. Nature Communications, 12(1), 1864. https://doi.org/10.1038/s41467-021-22126-y
Breyne, K., Ughetto, S., Rufino-Ramos, D., Mahjoum, S., Grandell, E. A., de Almeida, L. P., & Breakefield, X. O. (2022). Exogenous loading of extracellular vesicles, virus-like particles, and lentiviral vectors with supercharged proteins. Communications Biology, 5(1), 516. https://doi.org/10.1038/s42003-022-03440-7
Cui, G. H., Guo, H. D., Li, H., Zhai, Y., Gong, Z. B., Wu, J., Liu, J. S., Dong, Y. R., Hou, S. X., & Liu, J. R. (2019). RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer’s disease. Immunity & Ageing, 16, 10. https://doi.org/10.1186/s12979-019-0150-2
Dar, G. H., Mendes, C. C., Kuan, W. L., Speciale, A. A., Conceição, M., Görgens, A., Uliyakina, I., Lobo, M. J., Lim, W. F., El Andaloussi, S., Mäger, I., Roberts, T. C., Barker, R. A., Goberdhan, D. C. I., Wilson, C., & Wood, M. J. A. (2021). GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain. Nature Communications, 12(1), 6666. https://doi.org/10.1038/s41467-021-27056-3
de Jong, O. G., Murphy, D. E., Mäger, I., Willms, E., Garcia-Guerra, A., Gitz-Francois, J. J., Lefferts, J., Gupta, D., Steenbeek, S. C., van Rheenen, J., El Andaloussi, S., Schiffelers, R. M., Wood, M. J. A., & Vader, P. (2020). A CRISPR-Cas9-based reporter system for single-cell detection of extracellular vesicle-mediated functional transfer of RNA. Nature Communications, 11(1), 1113. https://doi.org/10.1038/s41467-020-14977-8
Dutta, K., Savard, A., Reshke, R., Taylor, J. A., Armitage, B., De Felice, F. G., Munoz, D. P., & Gibbings, D. (2026). Screening extracellular vesicle-producing cells enables delivery of silencing RNAs to the kidney and brain in small and large animals. Cell Biomaterials, 2, 100424. https://doi.org/10.1016/j.celbio.2026.100424
Eckardt-Michel, J., Lorek, M., Baxmann, D., Grunwald, T., Keil, G. M., & Zimmer, G. (2008). The fusion protein of respiratory syncytial virus triggers p53-dependent apoptosis. Journal of Virology, 82(7), 3236–3249. https://doi.org/10.1128/JVI.01887-07
Elia, C. A., Tamborini, M., Rasile, M., Desiato, G., Marchetti, S., Swuec, P., Mazzitelli, S., Clemente, F., Anselmo, A., Matteoli, M., & Verderio, C. (2019). Intracerebral injection of extracellular vesicles from mesenchymal stem cells exerts reduced Aβ plaque burden in early stages of a preclinical model of Alzheimer’s disease. Cells, 8(9), 1059. https://doi.org/10.3390/cells8091059
Ghosal, S., Bodnár, B. R., Kestecher, B. M., Nagy, Á., László, T., Yilmaz, B., Zeng, Y., Szabó, A., Bödör, C., Buzás, E. I., & Osteikoetxea, X. (2025). Revolutionizing therapeutics: Unleashing the power of extracellular vesicles for disease intervention. Current Opinion in Physiology, 43, 100815. https://doi.org/10.1016/j.cophys.2025.100815
Ghosh, M., Bayat, A.-H., & Pearse, D. D. (2025). Small extracellular vesicles in neurodegenerative disease: Emerging roles in pathogenesis, biomarker discovery, and therapy. International Journal of Molecular Sciences, 26(15), 7246. https://doi.org/10.3390/ijms26157246
Gu, L., Liu, J., Wang, C., Shan, X., Li, S., Zhang, X., Xia, L., & Li, J. (2026). Non-viral and local delivery of siRNA for Alzheimer’s disease treatment. International Journal of Pharmaceutics: X, 11, 100503. https://doi.org/10.1016/j.ijpx.2026.100503
Han, J., Sul, J. H., Lee, J., Kim, E., Kim, H. K., Chae, M., Lim, J., Kim, J., Kim, C., Kim, J.-S., Cho, Y., Park, J. H., Cho, Y. W., & Jo, D.-G. (2024). Engineered exosomes with a photoinducible protein delivery system enable CRISPR-Cas–based epigenome editing in Alzheimer’s disease. Science Translational Medicine, 16(759), eadi4830. https://doi.org/10.1126/scitranslmed.adi4830
Hao, Y., Su, C., Liu, X., Sui, H., Shi, Y., & Zhao, L. (2022). Bioengineered microglia-targeted exosomes facilitate Aβ clearance via enhancing activity of microglial lysosome for promoting cognitive recovery in Alzheimer’s disease. Biomaterials Advances, 136, 212770. https://doi.org/10.1016/j.bioadv.2022.212770
Inano, S., Kitano, T., & Nakase, I. (2024). A modified CD9 tag for efficient protein delivery via extracellular vesicles. PLoS ONE, 19(9), e0310083. https://doi.org/10.1371/journal.pone.0310083
Jiang, S., Cai, G., Yang, Z., Shi, H., Zeng, H., Ye, Q., Hu, Z., & Wang, Z. (2024). Biomimetic nanovesicles as a dual gene delivery system for the synergistic gene therapy of Alzheimer’s disease. ACS Nano, 18(18), 11753–11768. https://doi.org/10.1021/acsnano.3c13150
Joshi, B. S., de Beer, M. A., Giepmans, B. N. G., & Zuhorn, I. S. (2020). Endocytosis of extracellular vesicles and release of their cargo from endosomes. ACS Nano, 14(4), 4444–4455. https://doi.org/10.1021/acsnano.9b10033
Jurcau, M. C., Andronie-Cioara, F. L., Jurcau, A., Marcu, F., Tit, D. M., Pascalau, N., & Nistor-Cseppentö, D. C. (2022). The link between oxidative stress, mitochondrial dysfunction and neuroinflammation in the pathophysiology of Alzheimer’s disease: Therapeutic implications and future perspectives. Antioxidants, 11(11), 2167. https://doi.org/10.3390/antiox11112167
Kandeel, M., Morsy, M. A., Alkhodair, K. M., & Alhojaily, S. (2023). Mesenchymal stem cell-derived extracellular vesicles: An emerging diagnostic and therapeutic biomolecules for neurodegenerative disabilities. Biomolecules, 13(8), 1250. https://doi.org/10.3390/biom13081250
Kim, J., Hwang, Y. H., Nam, G.-H., & Kim, I.-S. (2026). Breaking barriers: Engineering extracellular vesicles for enhanced endosomal escape and therapeutic delivery. Journal of Controlled Release, 389, 114462. https://doi.org/10.1016/j.jconrel.2025.114462
Koeshermanto, T., Ferdiansyah, M. A., Tedjo, R. A. A., Azhara, A. Z., & Putra, S. E. (2026). Bridging the translational gap in Alzheimer’s disease: A bibliometric and evidence-based assessment of secretome and stem cell therapeutics. Archives of Gerontology and Geriatrics Plus, 3, 100295. https://doi.org/10.1016/j.aggp.2026.100295
Lee, B. K., Yoo, J.-R., & Jung, Y.-S. (2026). Platelet-derived granules and extracellular vesicles in neurodegenerative diseases: Neurovascular mechanisms and clinical implications. Cells, 15(7), 692. https://doi.org/10.3390/cells15070692
Li, H., Cao, Y., Ye, J., Yang, Z., Chen, Q., Liu, X., Zhang, B., Qiao, J., Tang, Q., Yang, H., Li, J., Shi, Z., & Mao, Y. (2023). Engineering brain-derived neurotrophic factor mRNA delivery for the treatment of Alzheimer’s disease. Chemical Engineering Journal, 466, 143152. https://doi.org/10.1016/j.cej.2023.143152
Li, W. (2004). GALA: A designed synthetic pH-responsive amphipathic peptide with applications in drug and gene delivery. Advanced Drug Delivery Reviews, 56(7), 967–985. https://doi.org/10.1016/j.addr.2003.10.041
Liang, X., Gupta, D., Xie, J., Van Wonterghem, E., Van Hoecke, L., Hean, J., Niu, Z., Ghaeidamini, M., Wiklander, O. P. B., Zheng, W., Wiklander, R. J., He, R., Mamand, D. R., Bost, J., Zhou, G., Zhou, H., Roudi, S., Estupiñán, H. Y., Rädler, J., Zickler, A. M., … El Andaloussi, S. (2025). Engineering of extracellular vesicles for efficient intracellular delivery of multimodal therapeutics including genome editors. Nature Communications, 16(1), 4028. https://doi.org/10.1038/s41467-025-59377-y
Mengesha, Y., Wondaya, M., Workye, M., & Belete, L. (2025). Extracellular vesicles as carriers for protein and peptide therapeutics delivery: A review. Intelligent Pharmacy, 3(4), 350–367. https://doi.org/10.1016/j.ipha.2025.05.001
Morishita, M., Takahashi, Y., Nishikawa, M., Ariizumi, R., & Takakura, Y. (2017). Enhanced class I tumor antigen presentation via cytosolic delivery of exosomal cargo by tumor-cell-derived exosomes displaying a pH-sensitive fusogenic peptide. Molecular Pharmaceutics, 14(11), 4079–4086. https://doi.org/10.1021/acs.molpharmaceut.7b00760
Munson, M. J., O’Driscoll, G., Silva, A. M., Lázaro-Ibáñez, E., Gallud, A., Wilson, J. T., Collén, A., Esbjörner, E. K., & Sabirsh, A. (2021). A high-throughput Galectin-9 imaging assay for quantifying nanoparticle uptake, endosomal escape and functional RNA delivery. Communications Biology, 4(1), 211. https://doi.org/10.1038/s42003-021-01728-8
Nakase, I., & Futaki, S. (2015). Combined treatment with a pH-sensitive fusogenic peptide and cationic lipids achieves enhanced cytosolic delivery of exosomes. Scientific Reports, 5, 10112. https://doi.org/10.1038/srep10112
Nakase, I., Noguchi, K., Aoki, A., Takatani-Nakase, T., Fujii, I., & Futaki, S. (2017). Arginine-rich cell-penetrating peptide-modified extracellular vesicles for active macropinocytosis induction and efficient intracellular delivery. Scientific Reports, 7, 1991. https://doi.org/10.1038/s41598-017-02014-6
Noguchi, K., Obuki, M., Sumi, H., Klußmann, M., Morimoto, K., Nakai, S., Hashimoto, T., Fujiwara, D., Fujii, I., Yuba, E., Takatani-Nakase, T., Neundorf, I., & Nakase, I. (2021). Macropinocytosis-inducible extracellular vesicles modified with antimicrobial protein CAP18-derived cell-penetrating peptides for efficient intracellular delivery. Molecular Pharmaceutics, 18(9), 3290–3301. https://doi.org/10.1021/acs.molpharmaceut.1c00244
Scrivo, A., Bernardino, L., & Consiglio, A. (2026). The dual role of glial extracellular vesicles in neurodegeneration: Insights from iPSC-based models. International Journal of Molecular Sciences, 27(11), 5182. https://doi.org/10.3390/ijms27115182
Shahlaei, M., Afkhami, H., Ahmadieh-Yazdi, A., Mirmazloumi, S. H., Sahraei, S. S., Akbari, M., Yang, P., Manoochehri, H., Tanzadehpanah, H., Mahaki, H., Sundararaman, A., Mohan, S., Sheykhhasan, M., Al-Musawi, S., & Dama, P. (2025). Exosomes in Alzheimer’s disease: From pathogenesis to therapeutics—A comprehensive review of diagnostic and drug delivery applications. Biomedicine & Pharmacotherapy, 192, 118548. https://doi.org/10.1016/j.biopha.2025.118548
Stein, J. B., Arif, M., Cheung, H., & Lee, K.-B. (2026). Advanced engineering strategies of extracellular vesicles for enhanced central nervous system regeneration and disease modulation. Cellular and Molecular Life Sciences, 83, 100495. https://doi.org/10.1016/j.celbio.2026.100495
Sun, C., Sha, S., Shan, Y., Gao, X., Li, L., Xing, C., Guo, Z., Du, H., & Wang, L. (2025). Intranasal delivery of BACE1 siRNA and berberine via engineered stem cell exosomes for the treatment of Alzheimer’s disease. International Journal of Nanomedicine, 20, 5873–5891. https://doi.org/10.2147/IJN.S481234
Teo, S. L. Y., Rennick, J. J., Yuen, D., Al-Wassiti, H., Johnston, A. P. R., & Pouton, C. W. (2021). Unravelling cytosolic delivery of cell penetrating peptides with a quantitative endosomal escape assay. Nature Communications, 12(1), 3721. https://doi.org/10.1038/s41467-021-23997-x
Wang, L., Mao, L., & Zong, X. (2026). Extracellular vesicles in Alzheimer’s disease: Mechanisms, biomarkers, and therapeutic engineering. International Journal of Molecular Sciences, 27(9), 3974. https://doi.org/10.3390/ijms27093974
Xiao, P., Wang, H., Liu, H., Yuan, H., Guo, C., Feng, Y., Qi, P., Yin, T., Zhang, Y., He, H., Tang, X., & Gou, J. (2024). Milk exosome–liposome hybrid vesicles with self-adapting surface properties overcome the sequential absorption barriers for oral delivery of peptides. ACS Nano, 18(33), 21091–21111. https://doi.org/10.1021/acsnano.4c02560
Xie, X., Song, Q., Dai, C., Cui, S., Tang, R., Li, S., Chang, J., Li, P., Wang, J., Li, J., & Zhang, Y. (2023). Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer’s disease: A phase I/II clinical trial. General Psychiatry, 36(5), e101143. https://doi.org/10.1136/gpsych-2023-101143
Zhao, M., Li, H., Ma, Y., Guo, Z., Liu, H., Guo, L., Ning, J., Zhang, W., Qin, W., Xie, W., & Kang, C. (2020). Engineering blood exosomes for tumor-targeting efficient gene/chemo combination therapy. Theranostics, 10(17), 7889–7905. https://doi.org/10.7150/thno.45028
Zhou, X., Liu, X., & Yao, K. (2026). Preparation, loading strategies, and therapeutic applications of extracellular vesicles for nucleic acid delivery. Molecular Therapy - Nucleic Acids, 37, 102870. https://doi.org/10.1016/j.omtn.2026.102870
Zhou, X., Miao, Y., Wang, Y., He, S., Guo, L., Mao, J., Chen, M., Yang, Y., Zhang, X., & Gan, Y. (2022). Tumour-derived extracellular vesicle membrane hybrid lipid nanovesicles enhance siRNA delivery by tumour-homing and intracellular freeway transportation. Journal of Extracellular Vesicles, 11(2), e12195. https://doi.org/10.1002/jev2.12195
Zhuo, Y., Luo, Z., Zhu, Z., Wang, J., Li, X., Zhang, Z., Guo, C., Wang, B., Nie, D., Gan, Y., Hu, G., & Yu, M. (2024). Direct cytosolic delivery of siRNA via cell membrane fusion using cholesterol-enriched exosomes. Nature Nanotechnology, 19(12), 1858–1868. https://doi.org/10.1038/s41565-024-01785-0
Zomer, A., Maynard, C., Verweij, F. J., Kamermans, A., Schäfer, R., Beerling, E., Schiffelers, R. M., de Wit, E., Berenguer, J., Ellenbroek, S. I. J., Wurdinger, T., Pegtel, D. M., & van Rheenen, J. (2015). In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell, 161(5), 1046–1057. https://doi.org/10.1016/j.cell.2015.04.042
Zomer, A., Steenbeek, S. C., Maynard, C., & van Rheenen, J. (2016). Studying extracellular vesicle transfer by a Cre-loxP method. Nature Protocols, 11(1), 87–101. https://doi.org/10.1038/nprot.2015.138
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