Trypsin-responsive biomimetic nanoparticles for synergistic antioxidant, anti-inflammatory, and islet-protective therapy in acute pancreatitis.

Acute pancreatitis (AP) is a rapidly progressing abdominal inflammatory disease associated with high morbidity and mortality, yet current pharmacological interventions remain limited and largely palliative. Herein, we developed a biomimetic, trypsin-responsive nanoparticle system (ФNM@BRZ) for targeted bilirubin delivery and multi-mechanistic therapeutic intervention in AP. The system comprises zein-based nanoparticles loaded with bilirubin and camouflaged with neutrophil membranes to enable inflammation-specific targeting via chemotactic mimicry. Upon reaching the inflamed pancreas, the overexpressed trypsin degrades the zein matrix, triggering site-specific release of bilirubin while concurrently suppressing protease activity by consuming trypsin. The trypsin-responsive nature of the formulation was supported by structural alteration of the nanoparticles within 1 h under a defined trypsin-rich condition, together with sustained bilirubin release over 72 h. Both in vitro and in vivo studies demonstrated that ФNM@BRZ exerted potent antioxidant and anti-inflammatory effects, effectively preserving islet integrity and function. These findings suggest that ФNM@BRZ represents a promising multifunctional nanotherapeutic platform for improving treatment outcomes in acute pancreatitis.