Piezoelectric nanozymes: a new frontier for next-generation tumor therapeutics

Abstract Cancer remains a critical global health challenge, leading to millions of deaths worldwide due to its rapid progression and complex resistance mechanisms. However, conventional therapeutic modalities are frequently constrained by tumor hypoxia, heterogeneity, therapeutic resistance, and off-target toxicity, emphasizing the necessity for robust and precise therapeutic approaches. Development of nanozyme-based approaches has provided innovative avenues for catalytic cancer therapy. However, the therapeutic capability of traditional approaches is often hindered by low catalytic efficiency and minimal production of reactive oxygen species (ROS) within the tumor microenvironment (TME). Consequently, piezoelectric nanozymes have emerged as a next-generation category of multifunctional nanocatalysts that integrate enzyme-mimicking catalytic activity with piezoelectric energy conversion, enabling effective and accurate tumor treatment under external mechanical stimulation. Piezoelectric polarization-mediated enhanced charge separation facilitates catalytic amplification, ROS generation, enhanced electron (e − ) transfer, and redox regulation, thereby addressing major constraints associated with conventional therapeutic techniques. This review comprehensively describes the charge-generating properties of piezoelectric materials with enzyme-mimicking catalytic activity, catalytic mechanisms, design strategies and current advancements in piezoelectric nanozyme-driven cancer therapy. Sonodynamic therapy (SDT), ferroptosis therapy, radiocatalytic therapy(RCT), starvation therapy (ST), piezocatalytic therapy(PCT), chemodynamic therapy (CDT), immunotherapy, and their synergistic combinations are all discussed in detail. Piezoelectric nanozymes offer a versatile platform for multimodal cancer therapy and represent a promising paradigm for developing strategies for precise, non-invasive cancer therapy through localized ROS generation and modulation of the TME.