Macrophage-mimicking nanotherapy for attenuation of acute pancreatitis

Abstract

Acute pancreatitis (AP) is a highly fatal pancreatic inflammation. In recent years, synthetic nanoparticles have been extensively developed as drug carriers to address the challenges of systemic adverse reactions and lack of specificity in drug delivery. However, systemically administered nanoparticle therapy is rapidly cleared from circulation by the mononuclear phagocyte system (MPS), leading to suboptimal drug concentrations in inflamed tissues and suboptimal pharmacokinetics. To address this challenge, we herein demonstrate a surface masking strategy that involves coating the surface of selenylated Poria cocos polysaccharide nanoparticles with a layer of macrophage plasma membrane to circumvent MPS sequestration, thereby enhancing the therapeutic efficacy of selenylated Poria cocos polysaccharide nanoparticles. Nanoparticles encapsulated with macrophage membranes can simulate the active homing efficacy of macrophages to inflamed lesions during AP, resulting in excessive infiltration of macrophages in pancreatic inflammation sites and prolonged tissue retention time. This technique converts non-adhesive lipid nanoparticles into bioadhesive nanoparticles, increasing local tissue accumulation under inflammatory conditions, including the pancreas and vulnerable lungs. The mechanism is related to targeting pro-inflammatory macrophages. In murine models of mild and severe AP, intravenous treatment with macrophage-mimicking nanoparticles effectively reduces systemic inflammation level and diminishes the recruitment of macrophages and neutrophils. Mechanistic studies elucidate that macrophage membrane-biomimetic selenylated Poria cocos polysaccharide nanoparticles primarily mitigate pancreatic inflammation by inhibiting the AKT/mTOR pathway to reverse autophagic flux impairment. This allows us to envision that the developed biomimetic nanotherapy approach could potentially serve as a novel strategy for pancreatic drug therapy.