ArticlePublished: 18 March 2026Qiangqiang Shi ORCID: orcid.org/0009-0009-2503-43741 na1,Ningqiang Gong ORCID: orcid.org/0000-0002-9444-85051,2 na1,Jinjin Wang ORCID: orcid.org/0000-0001-8382-044X1,Rohan Palanki1,Qiuxian Zheng3,Mohamad-Gabriel Alameh ORCID: orcid.org/0000-0002-5672-69304,Garima Dwivedi4,Benjamin Davis4,Jilian Melamed4,Zhangyi Luo ORCID: orcid.org/0009-0007-5791-40131,Junchao Xu ORCID: orcid.org/0000-0003-0725-81111,Christian G. Figueroa-Espada ORCID: orcid.org/0000-0003-2700-76781,Lulu Xue ORCID: orcid.org/0000-0001-5719-13361,Ye Zeng ORCID: orcid.org/0000-0003-1207-64861,Xuexiang Han ORCID: orcid.org/0000-0003-0011-52221,Dongyoon Kim1,Qinyuan Chen5,Hannah Yamagata ORCID: orcid.org/0000-0002-9525-71021,Hannah C. Geisler ORCID: orcid.org/0000-0001-6455-81831,Rakan El-Mayta ORCID: orcid.org/0000-0002-5855-233X4,Il-Chul Yoon1,Drew Weissman ORCID: orcid.org/0000-0002-1501-65104,6 &…Michael J. Mitchell ORCID: orcid.org/0000-0002-3628-22441,4,6,7,8,9 Nature Nanotechnology (2026)Cite this articleSubjectsDrug deliveryNanoparticlesAbstractRegulating T cell phenotypes between activation and exhaustion remains a significant challenge for messenger RNA-based cancer immunotherapy. A potential approach to improve anti-cancer T cell activity is to co-deliver interleukin-12 (IL-12), to stimulate effector T cells, and indoleamine 2,3-dioxygenase (IDO) inhibitor, to suppress T cell exhaustion. Here we design prodrug ionizable lipid nanoparticles (pLNPs), via a library of prodrug ionizable lipids (pILs), incorporating an intracellularly cleavable IDO inhibitor within the pIL structure and encapsulating IL-12 messenger RNA. The lead pIL shows enhanced mRNA transfection over a clinically utilized ionizable lipid, as well as strong immunomodulatory effects via release of the IDO inhibitor. In a subcutaneous colon cancer mouse model, pLNP drives complete regression of primary tumours by eliciting effector T cell infiltration while reducing exhaustion, induces a memory T cell response and stimulates a systemic immune response that allows for regression of distal tumours in this study. These results highlight the promise of pLNPs for small-molecule drug and mRNA combination cancer immunotherapy.This is a preview of subscription content, access via your institutionAccess optionsAccess Nature and 54 other Nature Portfolio journalsGet Nature+, our best-value online-access subscription27,99 € / 30 dayscancel any timeLearn moreSubscribe to this journalReceive 12 print issues and online access269,00 € per yearonly 22,42 € per issueLearn moreBuy this articlePurchase on SpringerLinkInstant access to the full article PDF.39,95 €Prices may be subject to local taxes which are calculated during checkoutFig. 1: Engineering IDO inhibitor-based prodrug ionizable lipids (pILs) to facilitate IL-12 mRNA delivery via prodrug lipid nanoparticles (pLNPs) for synergistic cancer immunotherapy.Fig. 2: In vitro and in vivo screening of pIL library and lead pLNPs for mRNA delivery.Fig. 3: G0-SS-AA-C12 LNP for potent IL-12 mRNA transfection and suppression of T cell exhaustion in vitro.Fig. 4: G0-SS-AA-C12 IL-12 pLNP achieves synergistic therapeutic effects in vivo in an MC38 tumour model and induces a splenic T cell response.Fig. 5: Characterization of TME after treatment with G0-SS-AA IL-12 pLNPs encapsulating IL-12 mRNA.Fig. 6: Intratumoural injection of G0-SS-AA-C12 IL-12 pLNP elicits effective long-term anti-tumour response and drives regression of distal tumours.Data availabilityAll relevant data supporting the findings of this study are available within the paper, Supplementary Information or Source Data file. 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Drug Discov. 23, 607–625 (2024).Article CAS PubMed Google Scholar Download referencesAcknowledgementsM.J.M. acknowledges support from a Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI), a US National Science Foundation CAREER award (CBET-2145491) and an American Cancer Society Research Scholar Grant (RSG-22-122-01-ET).Author informationAuthor notesThese authors contributed equally: Qiangqiang Shi, Ningqiang Gong.Authors and AffiliationsDepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA, USAQiangqiang Shi, Ningqiang Gong, Jinjin Wang, Rohan Palanki, Zhangyi Luo, Junchao Xu, Christian G. Figueroa-Espada, Lulu Xue, Ye Zeng, Xuexiang Han, Dongyoon Kim, Hannah Yamagata, Hannah C. Geisler, Il-Chul Yoon & Michael J. MitchellDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Science at Microscale, University of Science and Technology of China, Hefei, ChinaNingqiang GongDepartment of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USAQiuxian ZhengDepartment of Medicine, University of Pennsylvania, Philadelphia, PA, USAMohamad-Gabriel Alameh, Garima Dwivedi, Benjamin Davis, Jilian Melamed, Rakan El-Mayta, Drew Weissman & Michael J. MitchellSchool of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USAQinyuan ChenInstitute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADrew Weissman & Michael J. MitchellPenn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USAMichael J. MitchellAbramson Cancer Center, 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. MitchellAuthorsQiangqiang ShiView author publicationsSearch author on:PubMed Google ScholarNingqiang GongView author publicationsSearch author on:PubMed Google ScholarJinjin WangView author publicationsSearch author on:PubMed Google ScholarRohan PalankiView author publicationsSearch author on:PubMed Google ScholarQiuxian ZhengView author publicationsSearch author on:PubMed Google ScholarMohamad-Gabriel AlamehView author publicationsSearch author on:PubMed Google ScholarGarima DwivediView author publicationsSearch author on:PubMed Google ScholarBenjamin DavisView author publicationsSearch author on:PubMed Google ScholarJilian MelamedView author publicationsSearch author on:PubMed Google ScholarZhangyi LuoView author publicationsSearch author on:PubMed Google ScholarJunchao XuView author publicationsSearch author on:PubMed Google ScholarChristian G. Figueroa-EspadaView author publicationsSearch author on:PubMed Google ScholarLulu XueView author publicationsSearch author on:PubMed Google ScholarYe ZengView author publicationsSearch author on:PubMed Google ScholarXuexiang HanView author publicationsSearch author on:PubMed Google ScholarDongyoon KimView author publicationsSearch author on:PubMed Google ScholarQinyuan ChenView author publicationsSearch author on:PubMed Google ScholarHannah YamagataView author publicationsSearch author on:PubMed Google ScholarHannah C. GeislerView author publicationsSearch author on:PubMed Google ScholarRakan El-MaytaView author publicationsSearch author on:PubMed Google ScholarIl-Chul YoonView author publicationsSearch author on:PubMed Google ScholarDrew WeissmanView author publicationsSearch author on:PubMed Google ScholarMichael J. MitchellView author publicationsSearch author on:PubMed Google ScholarContributionsQ.S., N.G. and M.J.M. conceived and designed the experiments. Q.S., N.G., J.W., Q.Z., M.-G.A., G.D., B.D., J.M., Z.L., R.P., J.X., Y.Z., L.X., X.H., D.K., Q.C., H.Y., H.C.G., R.E.-M. and I.-C.Y. performed the experiments. Q.S., N.G. and M.J.M. analysed the data. Q.S., R.P., C.G.F.-E., H.C.G., D.W. and M.J.M. wrote, reviewed and edited the paper. M.J.M. supervised the entire project. All authors discussed the results and commented on the paper.Corresponding authorCorrespondence to Michael J. Mitchell.Ethics declarationsCompeting interestsM.J.M. and Q.S. have filed a patent application based on this study (Application No. PCT/US25/52032). The other authors declare no competing interests.Peer reviewPeer review informationNature Nanotechnology thanks Philippe Barthélémy and Quanyin Hu for their contribution to the peer review of this work.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary Information (download PDF )Expanded materials and methods, Figs. 1–90 and Table 1.Reporting Summary (download PDF )Source dataSource Data Fig. 2 (download XLSX )Statistical source data.Source Data Fig. 3 (download XLSX )Statistical source data.Source Data Fig. 4 (download XLSX )Statistical source data.Source Data Fig. 5 (download XLSX )Statistical source data.Source Data Fig. 6 (download XLSX )Statistical source data.Rights and permissionsSpringer 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 permissionsAbout this article