{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T12:20:58Z","timestamp":1788524458274,"version":"build-2803163510"},"reference-count":196,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of several hematological malignancies, but its broader application remains constrained by the complexity, cost, and time required for conventional ex vivo manufacturing.\n                    <jats:italic>In vivo<\/jats:italic>\n                    CAR T-cell therapy has emerged as a promising next-generation strategy that aims to generate CAR T cells directly within the patient through targeted delivery of CAR-encoding genetic information to endogenous T cells. This approach has the potential to simplify treatment workflows, shorten manufacturing timelines, reduce production costs, and improve the accessibility of CAR-based immunotherapy. In this review, we summarize the conceptual evolution from ex vivo to\n                    <jats:italic>in vivo<\/jats:italic>\n                    CAR T-cell therapy and discuss major delivery platforms for\n                    <jats:italic>in vivo<\/jats:italic>\n                    CAR T-cell generation, including engineered lentiviral vectors (LVs), adeno-associated viral vectors, lipid nanoparticles, polymeric nanoparticles, extracellular vesicles, and fusogenic nanovesicles. We further examine key translational challenges and corresponding optimization strategies, including approaches to improve T-cell targeting specificity and delivery controllability, reduce vector immunogenicity, enhance CAR expression persistence, mitigate safety concerns associated with ectopic transduction or genomic integration, and potentially overcome the physical, antigenic, and immunosuppressive barriers encountered in solid tumors. Finally, we summarize early clinical trial progress and discuss future directions for improving the safety, efficacy, and translational potential of\n                    <jats:italic>in vivo<\/jats:italic>\n                    CAR T-cell therapy. Overall,\n                    <jats:italic>in vivo<\/jats:italic>\n                    CAR T-cell therapy represents an important extension of adoptive cell therapy and may reshape the development and clinical implementation of cell-based immunotherapies.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1927594","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T12:01:20Z","timestamp":1788523280000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["In vivo CAR T-cell generation: delivery platforms, clinical progress, and translational barriers"],"prefix":"10.3389","volume":"17","author":[{"given":"Tianqun","family":"Huo","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Changzhou Hospital Affiliated to Nanjing University of Chinese Medicine","place":["Changzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongping","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Changzhou Hospital Affiliated to Nanjing University of Chinese Medicine","place":["Changzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Kong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2025.03.005","article-title":"From concept to cure: The evolution of CAR-T cell therapy","volume":"33","author":"Patel","year":"2025","journal-title":"Mol 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