Sono-mediated glutamine metabolic nanoplatform against liver fibrosis via breaking the vicious self-injury of activated hepatic stellate cells

Therapeutic-induced hepatocyte pyroptosis is often overlooked and leads to the release of inflammatory mediators, creating a vicious self-injury of the activated hepatic stellate cells (aHSCs) and fibrosis progression. Additionally, the dense extracellular matrix (ECM) serves as a barrier, significantly limiting the accessibility of therapeutics to aHSCs, presenting a challenge for effective anti-liver fibrosis therapies. Herein, we introduce an innovative dual-faceted strategy that focuses on regulating glutamine metabolism to disrupt the vicious cycle of inflammation, while leveraging ultrasound to improve drug accessibility to aHSCs. Porous coordination network nanoparticles (PCN-NPs) used as sonosensitizers were shown to soften and remodel the ECM through the rapid collapse of bubbles and the generation of shock waves and high pressure under ultrasound irradiation, facilitating increased accessibility of therapeutics to aHSCs. Furthermore, the glutamine metabolism inhibitor V-9302, delivered via PCN-NPs, induced apoptosis of aHSCs in a non-inflammatory manner, thereby breaking the pro-inflammatory vicious cycle. Hyaluronic acid-modified nanoparticles specifically targeted aHSCs by recognizing overexpressed CD44 receptors, resulting in significant amelioration of fibrosis in CCl 4 -induced fibrotic mice. This study underscores the critical role of regulating glutamine metabolism in terminating the vicious crosstalk between hepatocytes and hepatic stellate cells and presents a promising avenue for the development of antifibrotic therapies.