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While lymphoid tropism is essential, it is demonstrated that high tropism alone is insufficient for effective in vivo engineering\u2014some highly tropic LNPs frequently exhibit suboptimal T cell transfection. Crucially, intrinsic T cell transfection potency emerges as an orthogonal and equally critical determinant, consistent with the need for both T cell specificity and transfection efficiency. Through screening a tail\u2010varied ionizable lipid library, H\n                    <jats:sub>3<\/jats:sub>\n                    T\n                    <jats:sub>4<\/jats:sub>\n                    is identified, a citronellol\u2010tailed LNP with enhanced lymphoid tropism and superior intrinsic potency. The CD3\u2010targeted H\n                    <jats:sub>3<\/jats:sub>\n                    T\n                    <jats:sub>4<\/jats:sub>\n                    LNP (\u03b1H\n                    <jats:sub>3<\/jats:sub>\n                    T\n                    <jats:sub>4<\/jats:sub>\n                    ) achieves ~85% in vivo efficacy in T cell engineering, outperforming benchmark LNPs by \u223c50% (40% vs. 85%). This proposes a new optimization strategy: effective engineering requires balancing potency and tropism, not maximizing tropism alone. In murine CD19 solid tumor models, \u03b1H\n                    <jats:sub>3<\/jats:sub>\n                    T\n                    <jats:sub>4<\/jats:sub>\n                    \u2010generated CAR T cells achieved 83% tumor clearance, demonstrating potency\u2010driven efficacy. This work establishes intrinsic transfection potency as a primary tunable parameter for next\u2010generation CAR T platforms.\n                  <\/jats:p>","DOI":"10.1002\/smll.202509742","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T08:31:51Z","timestamp":1773304311000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Superior In Vivo Efficacy for T Cell Engineering via Citronellol\u2010Tailored mRNA\u2010tLNPs"],"prefix":"10.1002","volume":"22","author":[{"given":"Shuaijie","family":"Ji","sequence":"first","affiliation":[{"name":"State Key Laboratory of Green Pesticide, College of Chemistry Central China Normal University  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Deng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine For Cancer, Shanghai Cancer Institute, School of Medicine, Renji Hospital Shanghai Jiao Tong University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baoqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Green Pesticide, College of Chemistry Central China Normal University  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Green Pesticide, College of Chemistry Central China Normal University  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyan","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Green Pesticide, College of Chemistry Central China Normal University  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junlin","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine For Cancer, Shanghai Cancer Institute, 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