Abstract

Hepatocellular carcinoma (HCC) remains a challenge for therapeutic efficacy in converting cold tumors into hot ones. Herein, doping defect–engineered manganese perovskite piezoelectric nanocubes (Mn-BaZrO3, MBZO) integrated miltirone biomimetic delivery within tumor-derived nanovesicles are proposed for the parallel pyroptosis-apoptosis-necroptosis (PANoptosis) and the stimulator of interferon genes (STING) pathway activation to reshape the immune microenvironment, leading to tumor regression in HCC. Homologously targeting HCC cells, MBZO nanocubes accumulated and produced exogenous reactive oxygen species through the piezocatalytic effect. Specifically, miltirone accelerated oxidative stress amplification, potentially serving as an inducer of programmed cell death in HCC. Then, PANoptosis was activated to disrupt the cell barrier and release damage-associated molecular patterns, promoting immunogenicity. Concurrently, MBZO synergistically stimulated the STING pathway to evoke pro-inflammatory responses and elicit immunogenic cell death, triggering effector immune cell deployment (EICD). The piezobiomimetic delivery nanosystem bridged innate immunity activation and EICD to convert cold tumors into hot tumors and suppress tumor growth, thereby enhancing the efficacy of piezoimmunotherapy in HCC.