Inflammation-driven biomimetic nano-polyphenol drug delivery system alleviates severe acute pancreatitis by inhibiting macrophage PANoptosis and pancreatic enzymes oversecretion.

INTRODUCTION: Severe acute pancreatitis (SAP) is a critical inflammatory disease with high morbidity and mortality. Current treatments focused on symptomatic relief but failed to prevent inflammation progression in cellular level. OBJECTIVES: In order to develop an SAP-targeting drug delivery system to alleviate SAP in cellular level and illustrate its mechanism, we explored the use of proanthocyanidin (PYD) and pentoxifylline (PTX) loaded into macrophage membrane-coated self-assembly nanoparticles (FePTX@CM NPs) for targeted SAP treatment. The combination application of these two drugs was innovative in SAP aid. METHODS: We developed the NPs by self-assembly strategy and cell membrane coating. Its particle size and zeta potential were measured by dynamic light scatter (DLS). The morphology of the NPs was observed by transmission electron microscopy (TEM). And the encapsulation efficiency was evaluated by nano-flow cytometry. The total protein profile was determined via Coomassie brilliant blue. We explore the mechanism of our NPs against SAP in cellular and animal levels. Bioinformatics approaches, TEM, immunofluorescent assay and co-immunoprecipitation were performed to comprehensively explain the specific anti-SAP mechanism of FePTX@CM NPs. RESULTS: After inflammation-driven targeting, PYD in the NPs inhibited pancreatic amylase and lipase release by suppressing mitochondrial reactive oxygen species (mtROS)/Golgi stress, while PTX prevented SAP-associated macrophage PANoptosis by inhibiting Zbp1 signal pathway. The protection effect of these biomimetic NPs worked from different aspects to alleviate SAP symptoms and inflammation progression in relative cells. CONCLUSION: The FePTX@CM NPs demonstrated effective pancreas targeting, reduced systemic inflammation especially pro-inflammatory cell recruitment and activation, and minimized tissue damage in SAP mouse models, offering a promising therapeutic strategy for clinical SAP management.