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Immunotherapies such as chimeric antigen receptor T (CAR\u2010T) cell therapy have been remarkably effective in treating hematological cancers, but their efficacy is limited in solid tumors. Recently, CAR macrophages (CAR\u2010Ms) have emerged as a promising solid tumor immunotherapy, primarily for their intrinsic tumor infiltration and effector functions. However, CAR\u2010Ms are engineered using viral transduction, which is associated with aberrant immunogenicity and toxicity. To overcome these challenges, we developed a bioinspired oxidized lipid nanoparticle (LNP) platform for mRNA\u2010based engineering of human CAR\u2010Ms. A library of 24 ionizable lipids was synthesized, formulated into LNPs, and screened for delivery to human macrophages. The top LNP was subsequently optimized using an orthogonal design of experiments and the physicochemical properties, such as size and mRNA encapsulation, were tuned via optimization of microfluidic mixing parameters, yielding an LNP formulation that significantly outperformed a gold standard C12\u2010200 LNP. Utilizing small molecule and antibody inhibitors, we demonstrate that uptake of optimized LNPs into macrophages is driven by apolipoprotein E independent macropinocytosis, which is further supported by potent extrahepatic spleen tropism upon intravenous administration to mice. Lastly, we demonstrate the translatability of this LNP platform and utilize it to engineer functional primary human HER2\u2010CAR\u2010Ms ex vivo with potent antigen\u2010specific tumor cell killing, validated in an ex vivo co\u2010culture with ovarian cancer cells. This bioinspired oxidized LNP platform demonstrates potential for engineering a range of human CAR\u2010M immunotherapies to treat various types of solid tumors.<\/jats:p>","DOI":"10.1002\/btm2.70138","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T07:33:24Z","timestamp":1774856004000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Bioinspired oxidized\n                    <scp>mRNA<\/scp>\n                    lipid nanoparticles for ex vivo engineering of chimeric antigen receptor macrophages targeting solid tumors"],"prefix":"10.1002","volume":"11","author":[{"given":"Alvin J.","family":"Mukalel","sequence":"first","affiliation":[{"name":"Department of Bioengineering University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Tylek","sequence":"additional","affiliation":[{"name":"School of 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