Dopant‐Regulated Piezocatalysts Evoke Sonopiezoelectric and Enzymatic PANoptosis for Synergistic Cancer Therapy

Piezocatalyst-enabled sonopiezoelectric therapy offers noninvasive treatment with high spatiotemporal selectivity, yet existing piezocatalysts are limited by suboptimal efficacy, cancer cell resistance to oxidative stress, and biosafety concerns. Here, hafnia (HfO₂), one of the only few FDA-approved inorganic nanomaterials for clinical trials, is identified as a promising piezocatalyst with high translational potential for sonopiezoelectric and enzymatic PANoptosis-boosted nanocatalytic therapy. Specifically, engineered transition metal-substituted HfO₂ nanocatalysts are synthesized to optimize piezoelectric and enzyme-mimicking activities. Among these, Mn-substituted HfO₂ with a 20% Mn ratio (HMO) demonstrates superior performance in sono-triggered reactive oxygen species generation, attributed to its reduced bandgap and increased oxygen vacancies. HMO also exhibits multiple enzyme-mimicking activities, including peroxidase (POD), catalase (CAT), and glutathione peroxidase (GPx), amplifying oxidative stress through tumor-specific catalytic reactions. These dual catalytic effects enable the activation of cancer cell PANoptosis to elicit a robust antitumor immune response. Biological evaluations show significant tumor suppression and antitumor immune responses by HMO-mediated nanocatalytic therapy. Unlike utilizing the radiosensitization ability of HfO₂ in the clinic, this work unveils the distinctive sonopiezoelectric effect and multienzymatic activities of HfO₂-based nanocatalysts for biomedical applications, holding the potential to overcome the challenges of radiation damage associated with radiotherapy.