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Traditional approaches combining conventional immune checkpoint inhibitors with neoantigen vaccines have shown some promise in treating PDAC but are often compromised by intratumoral T lymphocyte exhaustion and systemic toxicity. Hence, novel approaches are needed to address these challenges. Herein, we demonstrate that mRNA polymeric nanoparticles encoding anti-PD-1 antibodies in situ at the tumor site enhance the therapeutic efficacy of neoantigen-based mRNA vaccine for PDAC. This mRNA-based, in situ anti-PD-1 antibody production strategy also protects tumor-infiltrating T cells from PD-1 inhibition, potentially reducing the toxicities induced by systemic checkpoint inhibition. 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