Gut microenvironment-responsive copper selenide/disulfiram/eudragit® L100-55 nanoflowers alleviate chronic pancreatitis via the inhibition of pyroptosis and pancreatic stellate cell activation.

Pyroptosis is involved in various inflammatory and fibrotic processes, but its specific role in the progression of chronic pancreatitis (CP) remains insufficiently explored. This study first investigated the dynamic expression changes of pyroptosis-related proteins during CP development and verified the regulatory effects of disulfiram (DSF) on key effector cells in CP, namely pancreatic stellate cells (PSCs) and macrophages. Building on these findings, a gut microenvironment-responsive nanoplatform, CuSe/DSF/EL nanoflowers, was designed and synthesized by integrating CuSe (as a carrier and selenium donor), DSF (as the core therapeutic agent), and Eudragit® L100-55 (EL, a pH-sensitive polymer for intestinal targeting). Results demonstrated that the CuSe/DSF/EL nanoflowers exhibited excellent biocompatibility, robust antioxidant capacity, and efficient electrostatic targeting to inflamed pancreatic tissues via charge interactions. In vivo experiments using a mouse CP model confirmed that the nanoflowers significantly alleviated pancreatic inflammation, fibrosis, and pyroptosis, while effectively repairing pancreatic structure and restoring its function. Further RNA sequencing (RNA-seq) analysis revealed that the nanoflowers reversed CP-associated transcriptomic dysregulation, with a notable focus on correcting impaired pancreatic secretion pathways. This study clarifies the critical role of pyroptosis in CP pathogenesis and provides a novel, multi-mechanistic nanotherapeutic strategy for CP treatment by enhancing the bioavailability and targeting efficiency of DSF.