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CARs, now in their fifth generation, are engineered by combining monoclonal antibody fragments with signaling and co-stimulatory domains and have been successfully applied to T cell, natural killer (NK) cell, and macrophage-based therapies. Notable clinical successes, such as tisagenlecleucel and lisocabtagene maraleucel underscore the therapeutic potential of CAR-T, CAR-NK and CAR-macrophages (CAR-Ms), which are currently being evaluated in numerous clinical trials. One promising extension of this approach involves the use of extracellular vesicles (EVs) derived from these immune cells. These nano-sized vesicles offer a cell-free platform to deliver diverse anticancer mediators, addressing the complex and dynamic nature of tumor environments. In this review, we examine the therapeutic potential and immunogenic properties of CAR-derived EVs, along with their role in modulating immune responses. Furthermore, we explore their application as targeted delivery vehicles for chemotherapeutic agents, with the goal of enhancing anti-tumor efficacy while minimizing systemic toxicity.<\/jats:p>","DOI":"10.3390\/ijms27052163","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T09:31:32Z","timestamp":1772098292000},"page":"2163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Harnessing CAR-Extracellular Vesicles for Next-Generation Cancer Immunotherapy"],"prefix":"10.3390","volume":"27","author":[{"given":"Sharenya","family":"Chelvaretnam","sequence":"first","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kol Thida","family":"Mom","sequence":"additional","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6182-7501","authenticated-orcid":false,"given":"Carlos Andres","family":"Palma Henriquez","sequence":"additional","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5303-9740","authenticated-orcid":false,"given":"Quang","family":"Pham","sequence":"additional","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amirah","family":"Fitri","sequence":"additional","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadman","family":"Bhuiyan","sequence":"additional","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mozhgan","family":"Shojaee","sequence":"additional","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kartini","family":"Asari","sequence":"additional","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiba","family":"Rashid","sequence":"additional","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leearne","family":"Hinch","sequence":"additional","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramin","family":"Khanabdali","sequence":"additional","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Rice","sequence":"additional","affiliation":[{"name":"INOVIQ Ltd., Melbourne, VIC 3168, Australia"},{"name":"Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Khan, S.H., Choi, Y., Veena, M., Lee, J.K., and Shin, D.S. 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