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However, efficient gene delivery to hard-to-transduce tissues\u2014including the retina, deep skeletal muscle, and the central nervous system\u2014remains a significant challenge, limited by structural barriers, preexisting immunity, and dose-dependent toxicities. This review systematically outlines recent advances in overcoming these delivery bottlenecks. We delve into four key strategic areas: (i) capsid engineering (\n                    <jats:italic toggle=\"yes\">e.g.<\/jats:italic>\n                    , rational design, directed evolution, and computational approaches) to enhance tropism and evade immune detection; (ii) innovative delivery routes (local, systemic, and physical\/chemical methods) to improve vector bioavailability; (iii) modulation of intracellular trafficking to boost nuclear delivery; and (iv) immunomodulatory strategies to mitigate both innate and adaptive immune responses. We further highlight translational progress in neuromuscular and retinal diseases and discuss persistent challenges. Looking forward, we envision that the convergence of next-generation capsids, smart vector systems, and integrated delivery platforms will be critical to expand the therapeutic landscape of AAVs from rare monogenic disorders to broader clinical applications.\n                  <\/jats:p>","DOI":"10.1177\/10430342261432669","type":"journal-article","created":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T05:59:20Z","timestamp":1775282360000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Adeno-Associated Virus Gene Delivery to Hard-to-Transduce Tissues: Biological Barriers, Engineering Strategies, and Clinical Challenges"],"prefix":"10.1177","author":[{"given":"Xiaoyu","family":"Nan","sequence":"first","affiliation":[{"name":"School of Biological Science and Medical Engineering, Hunan University of Technology, Zhuzhou, Hunan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiawen","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Hunan University of Technology, Zhuzhou, Hunan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunuo","family":"Jiao","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Hunan University of Technology, Zhuzhou, Hunan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wangan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Hunan University of Technology, Zhuzhou, Hunan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujuan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Hunan University of Technology, Zhuzhou, Hunan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yurong","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Medical Imaging, Hubei University of Science and Technology, Xianning, Hubei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Xu","sequence":"additional","affiliation":[{"name":"Zhuzhou People's Hospital, Zhuzhou, Hunan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Hunan University of Technology, Zhuzhou, Hunan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyan","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Biological Science and Medical Engineering, Hunan University of Technology, Zhuzhou, Hunan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Magnetic Resonance Spectroscopy and Imaging, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, Hubei, China."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.5.3994-4003.1999"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00895-06"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.79.6.2077"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.2.1438-1445.1998"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/4768"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31868-8"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1996.0367"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.71.9.6823-6833.1997"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.2.1309-1319.1999"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101559200"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2211644"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2113708"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.1.309-319.1998"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.182412299"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.12.6381-6388.2004"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02012-07"},{"issue":"4","key":"e_1_3_4_18_2","first-page":"781","article-title":"Engineered AAV13 variants with enhanced transduction and confined spread","volume":"45","author":"Luo NS","year":"2024","unstructured":"Luo NS, , Cai YX, , Han ZP, et al. 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