Self‐Assembled Ruthenium Complexes With Sonobleaching Ligand for Enhanced Tumor Penetration and Immunogenic Sonotherapy

Ruthenium complexes, which can be activated with precise light-induced spatiotemporal control, are recognized as promising candidates for cancer therapy. However, the inadequate tumor penetration and their dependence on light activation present challenges to deeper clinical application. Herein, we introduce a charge-reversal strategy to enhance tumor penetration and cellular uptake of RuIR783, a self-assembled metalloprodrug activated by ultrasound, thereby enabling deep tissue penetration. RuIR783 is synthesized by coordinating a Ru(II) polypyridyl complex with a heptamethine cyanine dye bearing two hydrophilic sulfonic groups. The cyanine dye component serves as both the ultrasound antenna and the self-assembly motif. RuIR783 self-assembles into large nanoparticles with negatively charged surfaces, facilitating their circulation in the bloodstream and accumulation at tumor sites. Upon ultrasound irradiation, the cyanine scaffold within the accumulated RuIR783 nanoparticles undergoes rapid sonobleaching, resulting in their transformation into smaller nanofragments with cationic surface charges. This transformation enhanced tumor penetration by 6.5-fold and cellular internalization by 4.2-fold. The generation of singlet oxygen and monocationic anticancer Ru complexes enhances the efficacy of immunogenic cell death through mitochondrial damage, achieving a 90.5% tumor inhibition rate. This study demonstrates the first ultrasound-mediated activation of metalloprodrugs for immunogenic tumor treatment through morphological transformation and charge reversal.