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It is hypothesized that overcoming these barriers requires a dual approach: inducing immunogenic tumor cell death (ICD) and enhancing the cancer immunity cycle by exogenous neoantigen targeting on the spleen. In this study, a novel strategy is presented combining irinotecan\u2010loaded silicasomes with spleen\u2010targeting lipid nanoparticles (LNPs) carrying KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    \u00a0mRNA and the toll\u2010like receptor 7\/8 (TLR7\/8) agonist 3M\u2010052. The goal is to establish a cancer immunity cycle by promoting endogenous tumor antigen release by the generation of KRAS\u2010specific cytotoxic T cells. Using an orthotopic PDAC mouse model, it is demonstrated that this dual\u2010platform approach significantly reduces tumor burden and extends survival compared to monotherapies. Bulk RNA sequencing and gene expression analyses further reveal synergy between the immune responses at the primary tumor site and the spleen, including maximal upregulation of apoptosis\u2010related genes, endoplasmic reticulum stress pathways, antigen presentation pathways, and T cell activation markers. These findings indicate that the combinatorial strategy effectively bridges innate and adaptive immunity. In conclusion, this study highlights the potential of nanocarrier\u2010based immunotherapy to enhance PDAC immunity by integrating ICD induction with systemic immune reprogramming, offering a promising avenue for improving treatment outcomes.\n                  <\/jats:p>","DOI":"10.1002\/advs.202504886","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T11:08:22Z","timestamp":1749726502000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["KRAS mRNA Spleen\u2010Targeting Lipid Nanoparticles Synergize with Irinotecan Silicasomes to Robustly Augment the Cancer Immunity Cycle in Pancreatic Cancer"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7125-6562","authenticated-orcid":false,"given":"Lijia","family":"Luo","sequence":"first","affiliation":[{"name":"Division of Nanomedicine Department of Medicine University of California  Los Angeles CA 90095 USA"},{"name":"California NanoSystems Institute University of California  Los Angeles CA 90095 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6647-0684","authenticated-orcid":false,"given":"Xiang","family":"Wang","sequence":"additional","affiliation":[{"name":"California NanoSystems Institute University of California  Los Angeles CA 90095 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7239-9426","authenticated-orcid":false,"given":"Yu\u2010Pei","family":"Liao","sequence":"additional","affiliation":[{"name":"Division of Nanomedicine Department of Medicine University of California  Los Angeles CA 90095 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5232-4686","authenticated-orcid":false,"given":"Andre E.","family":"Nel","sequence":"additional","affiliation":[{"name":"Division of Nanomedicine Department of Medicine University 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