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Here, OncoLRC is introduced, a rationally engineered, spleen\u2010tropic, one\u2010component lipid\u2010mRNA complex that selectively delivers mRNA to splenic APCs following systemic administration. Through a systemic screening and optimization process, a dimethylamino (DMA)\u2010lipidoid\u2010based OncoLRC formulation that achieves nearly exclusive spleen\u2010targeting mRNA delivery, outperforming its conventional four\u2010component lipid nanoparticle (LNP) formulation counterpart has been developed. Notably, OncoLRC requires a reduced lipid\u2010to\u2010mRNA weight ratio of 1.5:1 compared to the typical 10:1 ratio in standard LNPs. OncoLRC formulated with ovalbumin (OVA) mRNA (OncoLRC\n                    <jats:italic>\n                      <jats:sup>OVA<\/jats:sup>\n                    <\/jats:italic>\n                    ) promotes dendritic cell (DC) maturation and activation, eliciting robust antigen\u2010specific immune responses. Mechanistic studies suggest that splenic delivery is mediated primarily via macropinocytosis. Moreover, OncoLRC\n                    <jats:italic>\n                      <jats:sup>OVA<\/jats:sup>\n                    <\/jats:italic>\n                    enhances the secretion of endogenous cytokines such as IL\u201012, further stimulating T cell activation and cytotoxic activity. In the B16F10\u2010OVA cold tumor model, OncoLRC\n                    <jats:italic>\n                      <jats:sup>OVA<\/jats:sup>\n                    <\/jats:italic>\n                    demonstrates strong prophylactic antitumor efficacy and exhibits a profound synergistic effect when combined with immune checkpoint blockade therapy, leading to significant tumor growth inhibition. Collectively, our findings establish OncoLRC as a simple yet effective APC\u2010targeted mRNA delivery platform, highlighting its potential as a next\u2010generation mRNA cancer vaccine system.\n                  <\/jats:p>","DOI":"10.1002\/advs.202512535","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T03:35:31Z","timestamp":1763782531000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Rationally Engineered Spleen\u2010Tropic One\u2010Component Lipid\u2010mRNA Complex (OncoLRC) for Cancer Vaccines"],"prefix":"10.1002","volume":"13","author":[{"given":"Qimeng","family":"Yin","sequence":"first","affiliation":[{"name":"Human Phenome Institute Fudan University  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenchen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Human Phenome Institute Fudan University  Shanghai 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