Pyroptosis Induction with Nanosonosensitizer‐Augmented Sonodynamic Therapy Combined with PD‐L1 Blockade Boosts Efficacy against Liver Cancer

Abstract Induction of pyroptosis can promote anti‐PD‐L1 therapeutic efficacy due to the release of pro‐inflammatory cytokines, but current approaches can cause off target toxicity. Herein, a phthalocyanine‐conjugated mesoporous silicate nanoparticle (PMSN) is designed for amplifying sonodynamic therapy (SDT) to augment oxidative stress and induce robust pyroptosis in tumors. The sub‐10 nm diameter structure and c(RGDyC)‐PEGylated modification enhance tumor targeting and renal clearance. The unique porous architecture of PMSN doubles ROS yield and enhances pyroptotic cell populations in tumors (25.0%) via a cavitation effect. PMSN‐mediated SDT treatment efficiently reduces tumor mass and suppressed residual tumors in treated and distant sites by synergizing with PD‐L1 blockade (85.93% and 77.09%, respectively). Furthermore, loading the chemotherapeutic, doxorubicin, into PMSN intensifies SDT‐pyroptotic effects and increased efficacy. This is the first report of the use of SDT regimens to induce pyroptosis in liver cancer. This noninvasive and effective strategy has potential for clinical translation.