KRAS mRNA Spleen‐Targeting Lipid Nanoparticles Synergize with Irinotecan Silicasomes to Robustly Augment the Cancer Immunity Cycle in Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies due to its immunosuppressive tumor microenvironment. 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‐loaded silicasomes with spleen‐targeting lipid nanoparticles (LNPs) carrying KRAS G12D mRNA and the toll‐like receptor 7/8 (TLR7/8) agonist 3M‐052. The goal is to establish a cancer immunity cycle by promoting endogenous tumor antigen release by the generation of KRAS‐specific cytotoxic T cells. Using an orthotopic PDAC mouse model, it is demonstrated that this dual‐platform 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‐related 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‐based immunotherapy to enhance PDAC immunity by integrating ICD induction with systemic immune reprogramming, offering a promising avenue for improving treatment outcomes.