Strategically Engineered Ru(II) Complexes with Enhanced ROS Activity Enabling Potent Sonodynamic Effect against Multidrug-Resistant Biofilms

Sonodynamic therapy (SDT) can generate reactive oxygen species (ROS) to combat multidrug-resistant biofilms, which pose significant challenges to human health. As the key to producing ROS in SDT, the design of sonosensitizers with optimal molecular structures for sufficient ROS generation and activity in complex biofilm matrix is essential. In this study, we propose a π-expansion strategy and synthesize a series of small-molecule metal Ru(II) complexes (<b>Ru1</b>-<b>Ru4</b>) as sonosensitizers (<b>Ru1</b>-<b>Ru4</b>) to enhance the efficacy of SDT. Among these complexes, <b>Ru4</b> demonstrates remarkable ROS generation capability (∼65.5-fold) that surpasses most commercial sonosensitizers (1.3- to 6.7-fold). Through catalyzing endogenous H₂O₂ decomposition, <b>Ru4</b> facilitates the production of abundant O₂ as a resource for ¹O₂ and the generation of new ROS (i.e., ^•OH) for improving SDT. Furthermore, <b>Ru4</b> maintains the sustained ROS activity via consuming the interferences (e.g., glutathione) that react with ROS. Due to these unique advantages, <b>Ru4</b> exhibits potent biofilm eradication ability against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) both in vitro and in vivo, underscoring its potential use in clinical settings. This work introduces a new approach for designing effective sonosensitizers to eliminate biofilm infections, addressing a critical need in healthcare management.