A Pancreatitis‐Inspired Trypsinogen Nanoplatform Reprograms Tumor‐Associated Macrophages via NF‐κB for Pancreatic Cancer Immunotherapy

ABSTRACT Although reprogramming tumor‐associated macrophages (TAMs) represents a promising therapeutic strategy, approaches that are both precise and safe remain scarce. Inspired by the pro‐inflammatory M1‐like response triggered by trypsinogen in pancreatitis, trypsinogen as a novel macrophage reprogrammer is identified. Here, it is shown that trypsinogen drives M2‐to‐M1 repolarization via NF‐κB activation. To harness this activity, a pancreatitis‐inspired nanoplatform (JT@NPs‐aCD11b) co‐delivering trypsinogen and the CD47 inhibitor JQ1 to TAMs is developed. In pancreatic cancer models, JT@NPs‐aCD11b reprogrammed TAMs to an M1 phenotype while JQ1 blocked the “do not eat me” signal on cancer cells, synergistically enhancing phagocytosis. This strategy remodeled the immunosuppressive microenvironment, increased effector immune cells, and reduced suppressive populations, leading to potent tumor suppression, prolonged survival, and durable immune memory. Macrophage depletion abrogated efficacy, confirming TAMs as the primary mediators. This work establishes trypsinogen as a versatile immunomodulator and its nanoplatform as a promising strategy for pancreatic cancer immunotherapy.