De Novo Designed Ru(II) Metallacycle as a Microenvironment‐Adaptive Sonosensitizer and Sonocatalyst for Multidrug‐Resistant Biofilms Eradication

Albeit sonodynamic therapy (SDT) has achieved encouraging progress in microbial sterilization, the scarcity of guidelines for designing highly effective sonosensitizers and the intricate biofilm microenvironment (BME), substantially hamper the therapeutic efficacy against biofilm infections. To address the bottlenecks, we innovatively design a Ru(II) metallacycle‐based sonosensitizer/sonocatalyst (named Ru‐A3‐TTD) to enhance the potency of sonotherapy by employing molecular engineering strategies tailored to BME. Our approach involves augmenting Ru‐A3‐TTD’s production of ultrasonic‐triggered reactive oxygen species (ROS), surpassing the performance of commercial sonosensitizers, through a straightforward but potent π‐expansion approach. Within the BME, Ru‐A3‐TTD synergistically amplifies sonotherapeutic efficacy via triple‐modulated approaches: (i) effective alleviation of hypoxia, leading to increased ROS generation, (ii) disruption of the antioxidant defense system, which shields ROS from glutathione consumption, and (iii) enhanced biofilm penetration, enabling ROS production in deep sites. Notably, Ru‐A3‐TTD sono‐catalytically oxidizes NADPH, a critical coenzyme involved in antioxidant defenses. Consequently, Ru‐A3‐TTD demonstrates superior biofilm eradication potency against multidrug‐resistant Escherichia coli compared to conventional clinical antibiotics, both in vitro and in vivo. To our knowledge, this study represents the pioneering instance of a supramolecular sonosensitizer/sonocatalyst. It provides valuable insights into the structure‐activity relationship of sonosensitizers and paves a promising pathway for the treatment of biofilm infections.