Dual-responsive polypyridyl Ru(II)-scaffolded hydrogel for trinitarian tumor therapy activated by mono-wavelength photo-irradiation

Metal-coordinated hydrogels offer a strategy to integrate local drug retention, responsive release, and multimodal therapy, but assigning structural and therapeutic roles to a single metal complex remains challenging. Here, we report an injectable polypyridyl Ru(II)-scaffolded hydrogel, Ru(fmb)₃HADH-PDA@IR780, formed by dynamic Schiff-base crosslinking and loaded with polydopamine nanoparticles carrying IR780. In this platform, PDA@IR780 enables 808 nm near-infrared-activated photothermal and photodynamic outputs whereas the Ru(II) complex functions as both a hydrogel crosslinking unit and a redox-active therapeutic component. This formulation demonstrates dual pH/photo-responsiveness: acidic tumor microenvironment (TME) promoted formulation release, and NIR irradiation triggered rapid local heating and reactive oxygen species (ROS) generation. In vitro, the hydrogel produced enhanced tumor-cell killing through combined photothermal, photodynamic, and Ru-associated oxidative and chemodynamic therapy (CDT), accompanied by glutathione depletion and lipid-peroxidation-related stress. In vivo, local administration followed by short NIR irradiation markedly suppressed tumor growth, increased tumor-cell apoptosis, prolonged tumor-site retention, and showed no obvious short-term systemic toxicity under the tested regimen. Transcriptomic and histological analyses further suggested treatment-associated redox disruption and favorable modulation of the local immune microenvironment. This Ru(II)-scaffolded hydrogel provides a component-defined, single-wavelength-activated platform for locally retained multimodal tumor therapy. Notably, this work represents the first report of a polypyridyl Ru(II)-scaffolded hydrogel that unifies Ru(II)’s structural coordination with intrinsic therapeutic action, offering a translational strategy for synergistic, site-selective tumor therapy.