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Here, a structurally stabilized lipopolymer nanoparticle (LPNP) platform is proposed for in situ mRNA vaccination targeting antigen\u2010presenting cells (APCs). Central to this system is a rationally engineered double\u2010branched lipopolymer, P6CIT, whose unique molecular architecture enhances hydrophobic microviscosity and intermolecular packing, increasing particle rigidity and preventing premature disassembly in biological fluids. This stabilization enhances circulation stability and promotes favorable biodistribution to tumor sites and lymphoid organs, resulting in a 6.9\u2010fold increase in the spleen and a 13.6\u2010fold increase in lymph nodes, key sites for adaptive immune activation. Upon intratumoral administration, the LPNP co\u2010delivers mRNAs encoding tumor antigens and IL\u201012, synergistically reprogramming the TMEs and amplifying APC\u2010mediated T cell priming. In situ vaccination achieves a 42% complete response in a B16\u2010OVA melanoma model and outperforms ALC\u20100315 LNPs in wild\u2010type B16F10 tumors. This work highlights chemical\u2010level structural optimization enabling potent, simplified mRNA immunotherapy.<\/jats:p>","DOI":"10.1002\/adma.202520594","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T05:29:36Z","timestamp":1776835776000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Structurally Stabilized Lipopolymer Nanoplatform Targeting Pan\u2010Tissue Antigen\u2010Presenting Cells Enables Durable in situ mRNA Cancer Immunotherapy"],"prefix":"10.1002","volume":"38","author":[{"given":"Ling","family":"Zeng","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Medical Research Center Guangzhou Key Laboratory of Medical Nanomaterials Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou P. R. 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