{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T12:23:20Z","timestamp":1787660600431,"version":"build-2736575974"},"reference-count":139,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"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>Non-small cell lung cancer (NSCLC) remains difficult to treat with adoptive cell therapies because of antigen heterogeneity, immunosuppressive tumor microenvironments, stromal barriers, and manufacturing variability. Direct evidence for iPSC-derived CAR-NK EV\/sEV therapy in NSCLC is currently unavailable. Accordingly, this narrative review evaluates the platform as a translational hypothesis by integrating mechanistic evidence from CAR-engineered EV studies, biological-analog evidence from NK-cell EVs and other engineered EV systems, and clinical-analog evidence from living iPSC-NK or CAR-NK products. The proposed platform could combine a renewable producer-cell source, antigen-directed vesicle binding, and cytotoxic cargo delivery; however, each component, and particularly their integration into a single reproducible product, requires direct experimental validation. Compared with living cell products, CAR-NK sEVs may reduce selected risks related to cellular expansion, persistence, graft-versus-host disease, cytokine release syndrome, and neurotoxicity; however, they do not inherently eliminate antigen-dependent on-target\/off-tumor toxicity. Their nanoscale size is hypothesized to improve access to selected stromal barriers in preclinical models, but human solid-tumor penetration remains unproven. Major unresolved issues include rapid systemic clearance and sequestration by hepatic and splenic components of the mononuclear phagocyte system, route-dependent pulmonary deposition, mucus and mucociliary clearance, pulmonary macrophage uptake, subtype- and lesion-specific antigen heterogeneity, EV identity and purity, CAR-positive vesicle quantification, potency-adjusted manufacturing yield, lot comparability, and the absence of potency assays validated across laboratories or linked to clinical outcomes. Thus, iPSC-CAR-NK sEVs should currently be viewed as an investigational translational concept rather than a clinically ready NSCLC therapy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1934758","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:38:11Z","timestamp":1787657891000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["iPSC-derived CAR-NK extracellular vesicles for non-small cell lung cancer: evidence, engineering, and translational barriers"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhanhao","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Oncology, The First Affiliated Hospital of Dalian Medical University","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xutong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Oncology, The First Affiliated Hospital of Dalian 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