Activation of Metal Complexes With Ultrasound Waves for Targeted Anticancer Therapy

ABSTRACT Ultrasound technology has undergone a fundamental paradigm shift, evolving from a conventional diagnostic instrument into a sophisticated platform for non‐invasive, site‐specific cancer therapy. By harnessing the inverse piezoelectric effect, ultrasound generates mechanical waves that trigger acoustic cavitation in liquid media, producing localized hotspots of extreme temperature and pressure that can be exploited to activate rationally designed metal complexes through distinct and complementary mechanisms. This review provides a comprehensive analysis of two primary therapeutic modalities enabled by this approach. In sonodynamic therapy, metal centers function as sonosensitizers, generating cytotoxic reactive oxygen species through sonoluminescence‐mediated energy transfer. In ultrasound‐induced ligand release, the mechanochemical potential of metallocenes and coordination polymers is exploited, whereby cavitation‐induced shear forces drive heterolytic metal–ligand bond scission to achieve spatially controlled release of bioactive payloads and catalysts. A defining advantage of this platform over light‐based therapeutic modalities is its capacity to reach deep‐seated tumors. By synthesizing current structure–activity relationships and mechanistic understanding, this review establishes a rational design roadmap for next‐generation smart metal‐based prodrugs and delineates the critical challenges, including acoustic parameter standardization, long‐term metal fragment toxicology, and translational modeling fidelity, that must be addressed to advance this emerging field toward clinical application.