Fibrotic collagen-targeted delivery system blocks pancreatic intercellular crosstalk to alleviate pancreatic fibrosis.

Pancreatic fibrosis (PF) is a significant disruption of homeostasis in the pancreas, primarily characterized by excessive extracellular matrix (ECM) deposition due to pancreatic acinar cell (PAC) injury, pancreatic stellate cell (PSC) activation, and persistent inflammatory response. As a hallmark feature of both chronic pancreatitis and pancreatic cancer, progressive fibrosis exacerbates disease severity and poses significant clinical challenges. Notably, the self-amplifying crosstalk between activated PSCs and injured PACs perpetuates fibrogenesis and undermines therapeutic efficacy. However, currently, no effective strategy is available to modulate intercellular and alleviate pancreatic fibrosis. Herein, we developed dual drug-loaded lipid nanoparticles (JM-CCs) functionalized with a collagen-binding peptide (CBP) and collagenase I on their surface. This design facilitates targeted drug delivery by enabling penetration through the dense ECM barrier to the core of fibrotic lesions. The released melatonin alleviates oxidative stress in PACs, thereby reducing their fibrogenic stimulation of PSCs. Concurrently, the encapsulated JTE013 suppresses PSC activation by modulating autophagy, leading to decreased ECM production and mitigation of PAC injury. In a caerulein-induced PF mouse model, JM-CCs effectively reduce ECM deposition and repair pancreatic exocrine function. This study provides a novel strategy for regaining pancreatic tissue homeostasis and offers a promising approach for therapies of fibrosis and pancreatic disease.