Crosslinked ionizable lipids reprogram dendritic cell metabolism for potent mRNA vaccination

Nature Materials (2026)Cite this article Modulating metabolism in immune cells is an effective approach to induce desired immune responses. Here we develop a lipid nanoparticle (LNP) capable of metabolic reprogramming of dendritic cells for mRNA vaccine applications. Using imidoester-based conjugation chemistry, we design a crosslinked ionizable lipid, C12-2aN, which possesses intrinsic metabolic modulatory properties. This multifunctional ionizable lipid not only promotes effective mRNA expression by facilitating endosomal escape but also stimulates glycolysis through mTORC2 pathway activation. As both an mRNA carrier and a metabolic modulator, C12-2aN LNPs lead to potent vaccine efficacy in both SARS-CoV-2 and OVA cancer vaccine models, resulting in stronger neutralization of pseudovirus infection and improved survival rates, respectively, compared with control LNPs without the crosslinker. Moreover, C12-2aN LNPs outperformed FDA-approved LNPs in terms of reduced off-target delivery and lower immunogenicity. Overall, the integration of mRNA delivery and metabolic reprogramming induced by the ionizable lipid component presents significant potential for next-generation mRNA LNP vaccines.This is a preview of subscription content, access via your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $32.99 / 30 days cancel any timeSubscribe to this journal Receive 12 print issues and online access $259.00 per yearonly $21.58 per issueBuy this articleUSD 39.95Prices may be subject to local taxes which are calculated during checkoutThe data supporting the findings of this study are available within the Article and its Supplementary Information. Bulk RNA-sequencing data have been deposited in the NCBI Sequence Read Archive (accession number PRJNA1183400). 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Data for this manuscript were generated in the University of Pennsylvania’s CDB Microscopy Core and Small Animal Imaging Core Facility (RRID:SCR_022385). Data were also generated in the Penn Cytomics and Cell Sorting Shared Resource Laboratory at the University of Pennsylvania (RRID: SCR_022376) and the Pancreatic Islet Cell Biology Core, which is supported by the University of Pennsylvania Diabetes Research Center (DRC).These authors contributed equally: Dongyoon Kim, Ningqiang Gong.Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USADongyoon Kim, Ningqiang Gong, Emily L. Han, Jinjin Wang, Ellie Feng, Amanda M. Murray, Qiangqiang Shi, So-Jeong Moon, Kaitlin Mrksich & Michael J. MitchellDepartment of Pharmacy, Yonsei University, Incheon, Republic of KoreaDongyoon KimDepartment of Integrative Biotechnology, Yonsei University, Incheon, Republic of KoreaDongyoon KimDepartment of Medicine, University of Pennsylvania, Philadelphia, PA, USAMohamad-Gabriel AlamehDepartment Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, ChinaHanxun WangDepartment of Chemistry, University of Pennsylvania, Philadelphia, PA, USAIl-Chul YoonDepartment of HY-KIST Bio-Convergence, Hanyang University, Seoul, Republic of KoreaSo-Jeong MoonPenn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADrew Weissman & Michael J. MitchellCardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADrew Weissman & Michael J. MitchellInstitute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAMichael J. MitchellInstitute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAMichael J. MitchellAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USAMichael J. MitchellSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarD.K., N.G. and M.J.M. conceived the project and designed the experiments. The experiments were performed by D.K., N.G., M.-G.A., E.L.H., I.-C.Y., H.W., E.F., Q.S. and S.-J.M. and interpreted by all authors. D.K. prepared the figures and wrote the manuscript. D.K., E.L.H., J.W., A.M.M., E.F., K.M., D.W. and M.J.M. edited and revised the manuscript. All authors reviewed the manuscript and figures and approved the final version for submission.Correspondence to Michael J. Mitchell.D.K., N.G. and M.J.M. have filed a patent on the LNP technology discussed in this manuscript (application no. PCT/US25/51511). The remaining authors declare no competing interests.Nature Materials thanks John T. Wilson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary Notes 1–5, Figs. 1–39, methods, discussion and references.Statistical source data for the lipid-screening results.Statistical source data for the lipid-screening results.Statistical source data for the cellular metabolic activity results.Statistical source data for the in vivo biodistribution and safety analysis.Statistical source data for the SARS-CoV-2 vaccine study.Statistical source data for the cancer vaccine study.Unprocessed western blots.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.Reprints and permissionsKim, D., Gong, N., Alameh, MG. et al. Crosslinked ionizable lipids reprogram dendritic cell metabolism for potent mRNA vaccination. Nat. Mater. (2026). https://doi.org/10.1038/s41563-026-02512-xDownload citationReceived: 28 October 2024Accepted: 22 January 2026Published: 17 March 2026Version of record: 17 March 2026DOI: https://doi.org/10.1038/s41563-026-02512-xAnyone you share the following link with will be able to read this content:Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative