Abstract
Photodynamic-induced immunotherapy (PDI) is often hampered by low reactive oxygen species (ROS) yield, intra-tumor hypoxia, high glutathione (GSH) concentration, and immunosuppressive microenvironment. In view of this, a ruthenium (Ru)-based nanobattery (termed as IRD) with cascade-charged oxygen (O(2)), ROS, and photodynamic-induced immunotherapy by coordination-driven self-assembly of transition-metal Ru, photosensitizer indocyanine green (ICG), and organic ligand dithiobispropionic acid (DTPA). Then, IRD is camouflaged with macrophage membranes to obtain a nanobattery (termed as IRD@M) with targeting and immune evasion capabilities. Upon intravenous administration, IRD@M with a core-shell structure, nano diameter, and good stability can specifically hoard in tumor location and internalize into tumor cells. Upon disassembly triggered by GSH, the released Ru³⁺ not only catalyzes the conversion of endogenous hydrogen peroxide (H₂O₂) into O₂ to alleviate tumor hypoxia and reduce the expression of hypoxia-inducible factor-1α (HIF-1α), but also generates hydroxyl radicals (·OH) to elevate intracellular ROS levels. This process significantly enhances the photodynamic therapy (PDT) efficacy of the released ICG. Meanwhile, the released DTPA can significantly downregulate overexpressed GSH to reduce the elimination of ROS deriving from PDT by the exchange reaction of thiol-disulfide bond. It is also found that alleviating the hypoxic tumor microenvironment synergistically enhances the PDT efficacy, which in turn cascades to recharge the subsequent immune response, significantly improving the immunosuppressive tumor microenvironment and activating systemic tumor-specific immunity. Notably, in vitro and in vivo experimental results jointly confirm that such cascade-recharged macrophage-biomimetic Ru-based nanobattery IRD@M can achieve an obvious tumor elimination while results in a minimized side effect. Taken together, this work highlights a promising strategy for simple, flexible, and effective Ru-based immunogenic cell death (ICD) agents within PDI.