Engineering ruthenium(II)-based nanoparticles for synergistic sonodynamic therapy with multi-targeted redox catalysis

Sonodynamic therapy (SDT) could effectively overcomes the wavelength and energy limitations inherent to photodynamic therapy (PDT). However, current strategies for sonosensitizer optimization predominantly focus on acceptor engineering through extensive π-extension, which inadvertently compromises biocompatibility. Here, we first proposed a donor-engineering strategy by engineering conventional sp³-hybridized amino groups with sp² counterparts, forming the [Ru(tpy)(Aze-phen)Cl](PF₆) (complex 4). Complex 4 narrow the energy gap efficiently, achieving 1.6-fold higher NADH sonocatalytic oxidation efficiency than sp³-based analogues [Ru(tpy)(Meo-phen)Cl](PF₆) (complex 1), [Ru(tpy)(pip-phen)Cl](PF₆) (complex 2), and [Ru(tpy)(pyr-phen)Cl](PF₆) (complex 3). Self-assembly with DSPE-PEG2000 and complex 4 yields tumor-targeted nanoparticles, NanoRu, could be gathered in mitochondrion and cell nucleus. Functionally, NanoRu combinated SDT treatment exhibited synergized therapeutic effects on cancer cells with reduced growth of colongenic growth, increased ROS and lipid peroxidation, decreased GSH level. The irregulated ferroptosis, apoptosis, and DNA damage were indicated by altered protein expression of ACSL4 and GPX4, cleaved PARP and caspase 3, and γ-H2AX, respectively. Moreover, these nanoparticles under ultrasound irradiation induce significant regression of CT26 tumors with 83 % in mice. Together, our work establishes the first Ru(II)-based platform integrating donor engineering, multi-organelle targeting, and redox catalysis, overcoming chemoresistance while advancing precision sonodynamic-chemotherapy in colorectal cancer cells.