Ultrasmall Enzyodynamic PANoptosis Nano‐Inducers for Ultrasound‐Amplified Hepatocellular Carcinoma Therapy and Lung Metastasis Inhibition

Addressing the inefficiency of current therapeutic approaches for hepatocellular carcinoma is an urgent and pressing challenge. PANoptosis, a form of inflammatory programmed cell death, presents a dependable strategy for combating cancer by engaging multiple cell death pathways (apoptosis, pyroptosis, and necroptosis). In this study, an ultrasmall Bi₂Sn₂O₇ nanozyme with ultrasound-magnified multienzyme-mimicking properties is designed and engineered as a PANoptosis inducer through destroying the mitochondrial function of tumor cells and enhancing the intracellular accumulation of toxic reactive oxygen species, finally triggering the activation of PANoptosis process. The role of PANoptosis inducer has been verified by the expression of related proteins, including cleaved Caspase 3, NLRP3, N-GSDMD, cleaved Caspase 1, p-MLKL, and RIPK3. The inclusion of external ultrasonic irradiation significantly augments the enzyodynamic therapeutic efficiency. In vitro and in vivo antineoplastic efficacy, along with inhibition of lung metastasis, validate the benefits of the Bi₂Sn₂O₇-mediated PANoptosis pathway. This study not only elucidates the intricate mechanisms underlying Bi₂Sn₂O₇ as a PANoptosis inducer, but also offers a novel perspective for the treatment of hepatocellular carcinoma.