Pancreatic ductal adenocarcinoma (PDAC) features a profoundly immunosuppressive tumor microenvironment dominated by tumor-associated macrophages (TAMs), which facilitate immune evasion and compromise immunotherapeutic efficacy. The interaction between signal regulatory protein α (SIRPα) on macrophages and cluster of differentiation 47 (CD47) on tumor cells delivers a "don't-eat-me" signal that inhibits the phagocytosis of tumor cells by macrophages. Here, we present a macrophage-directed mRNA delivery strategy to reprogram TAMs in PDAC. Lipid nanoparticles (LNPs) were engineered to deliver inhibitor of DNA binding 3 (ID3) mRNA, whose expression was associated with reduced SIRPα expression and pro-inflammatory macrophage reprogramming. To promote preferential uptake by TAMs, mannose-modified LNPs (MLNPs) were developed by exploiting elevated CD206 expression on these cells. In an orthotopic PDAC model, MLNP-mediated ID3 mRNA delivery enhanced macrophage phagocytosis, promoted pro-inflammatory immune remodeling, and increased intratumoral T cell and natural killer cell (NK) infiltration, accompanied by tumor-growth suppression. Furthermore, MLNP-ID3 showed enhanced combination activity with anti-PD-1 therapy. Collectively, these findings establish a macrophage-targeted mRNA strategy for transcriptional reprogramming of TAMs and present a promising immunotherapeutic framework for PDAC.
