Strategically Engineered\nRu(II) Complexes with Enhanced\nROS Activity Enabling Potent Sonodynamic Effect against Multidrug-Resistant\nBiofilms

Sonodynamic therapy (SDT) can generate reactive oxygen\nspecies\n(ROS) to combat multidrug-resistant biofilms, which pose significant\nchallenges to human health. As the key to producing ROS in SDT, the\ndesign of sonosensitizers with optimal molecular structures for sufficient\nROS generation and activity in complex biofilm matrix is essential.\nIn this study, we propose a π-expansion strategy and synthesize\na 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)\nthat surpasses most commercial sonosensitizers (1.3- to 6.7-fold).\nThrough catalyzing endogenous H<sub>2</sub>O<sub>2</sub> decomposition, <b>Ru4</b> facilitates the production of abundant O<sub>2</sub> as\na resource for <sup>1</sup>O<sub>2</sub> and the generation of new\nROS (i.e., <sup>•</sup>OH) for improving SDT. Furthermore, <b>Ru4</b> maintains the sustained ROS activity via consuming the\ninterferences (e.g., glutathione) that react with ROS. Due to these\nunique advantages, <b>Ru4</b> exhibits potent biofilm eradication\nability against methicillin-resistant Staphylococcus\naureus (MRSA) both in vitro and in vivo, underscoring\nits potential use in clinical settings. This work introduces a new\napproach for designing effective sonosensitizers to eliminate biofilm\ninfections, addressing a critical need in healthcare management.