A Defect-Engineered Sono-Piezocatalytic In Situ Hydrogel for Preventing Hepatocellular Carcinoma Recurrence After Incomplete Radiofrequency Ablation.

Abstract

Residual tumor cells and the immunosuppressive microenvironment caused by incomplete radiofrequency ablation (iRFA) lead to hepatocellular carcinoma (HCC) recurrence. In this study, HA-V-MTO/LMP@Gel, an injectable sono-piezocatalytic hydrogel, is developed for local treatment of HCC after iRFA. It combines hyaluronic acid-modified, oxygen vacancy-engineered Mn-Ti metal-organic framework nanosheets (HA-V-MTO) with reactive oxygen species (ROS)-responsive liposomes co-loaded with STING agonist MSA-2 and an anti-PD-1 antibody (LMP) within a thermosensitive chitosan/β-glycerophosphate (CS/β-GP) hydrogel. Oxygen-vacancy engineering lowers the O₂ adsorption energy from 0.187 to -2.559 eV and raises the piezoelectric coefficient d₃₃ from 35.36 to 108.73 pm V^-1. Under ultrasound, HA-V-MTO generates ROS through sono-piezocatalysis, with an additional Fenton-like reaction from the Mn-containing framework. The resulting oxidative stress induces mitochondrial injury and promotes cytosolic mtDNA release, thereby facilitating cGAS-mediated STING activation. ROS-mediated LMP destabilization releases MSA-2, which further enhances STING signaling. The hydrogel undergoes temperature-triggered gelation for sustained local release. In a post-iRFA model, HA-V-MTO/LMP@Gel + US raises intratumoral IFN-β 7.9-fold, increases the proportion of mature dendritic cells to 50.8% and that of intratumoral CD8⁺ T cells to 26.5%, suppresses residual regrowth, prolongs survival, and protects against tumor rechallenge. This work presents a locally retained sono-piezocatalytic system that couples tumor killing with STING-driven immune activation after iRFA.