Journal article
Bioinspired oxidized mRNA lipid nanoparticles for ex vivo engineering of chimeric antigen receptor macrophages targeting solid tumors
Bioengineering & translational medicine, Forthcoming
30 Mar 2026
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Solid tumors remain difficult to treat via conventional and novel therapeutic strategies. Immunotherapies such as chimeric antigen receptor T (CAR‐T) cell therapy have been remarkably effective in treating hematological cancers, but their efficacy is limited in solid tumors. Recently, CAR macrophages (CAR‐Ms) have emerged as a promising solid tumor immunotherapy, primarily for their intrinsic tumor infiltration and effector functions. However, CAR‐Ms 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‐based engineering of human CAR‐Ms. 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 C12‐200 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‐CAR‐Ms ex vivo with potent antigen‐specific tumor cell killing, validated in an ex vivo co‐culture with ovarian cancer cells. This bioinspired oxidized LNP platform demonstrates potential for engineering a range of human CAR‐M immunotherapies to treat various types of solid tumors.
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Details
- Title
- Bioinspired oxidized mRNA lipid nanoparticles for ex vivo engineering of chimeric antigen receptor macrophages targeting solid tumors
- Creators
- Alvin J. Mukalel - University of PennsylvaniaTina Tylek - Drexel UniversityErin O'Brien - Drexel UniversityCaitlin Frazee - University of PennsylvaniaHannah C. Geisler - University of PennsylvaniaJacqueline Li - University of PennsylvaniaAjay S. Thatte - University of PennsylvaniaHannah C. Safford - University of PennsylvaniaChristian G. Figueroa-Espada - University of PennsylvaniaMohamad‐Gabriel Alameh - University of PennsylvaniaAlex G. Hamilton - University of PennsylvaniaDavid Mai - Parker Institute for Cancer ImmunotherapyNeil C. Sheppard - Parker Institute for Cancer ImmunotherapyCarl H. June - University of PennsylvaniaDrew Weissman - University of PennsylvaniaKara L. Spiller - Drexel UniversityMichael J. Mitchell (Corresponding Author) - University of Pennsylvania
- Publication Details
- Bioengineering & translational medicine, Forthcoming
- Publisher
- Wiley
- Number of pages
- 22
- Grant note
- Congressionally Directed Medical Research Programs: PR201467 Burroughs Wellcome FundNational Institutes of Health: DP2 TR002776 National Science Foundation: CBET-2145491
The authors acknowledge and thank the Penn Cytomics and Cell Sorting Core (RRID: SCR_022376). A.J.M, H.C.G, H.C.S., A.S.T., A.G.H., and C.G.F were supported by National Science Foundation Graduate Research Fellowships (Award 1845298). M.J.M. acknowledges support from a US National Institutes of Health (NIH) Director's New Innovator Award (DP2 TR002776), a Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI), a US National Science Foundation CAREER Award (CBET-2145491), the American Cancer Society (RSG-22-122-01-ET), and the Congressionally Directed Medical Research Programs [CDMRP] (PR201467).
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems; Chemical and Biological Engineering
- Web of Science ID
- WOS:001727238200001
- Scopus ID
- 2-s2.0-105034573720
- Other Identifier
- 991022172091504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biotechnology & Applied Microbiology
- Engineering, Biomedical
- Pharmacology & Pharmacy