Zero-Valent Ruthenium-Anchored Nanozymes Remodel Tumor Microenvironment for Malignant Tumor Treatment in Combination With αPD-L1 Immunotherapy.

The complex tumor microenvironment (TME) includes high concentrations of hydrogen peroxide, high expression of reduced glutathione (GSH), hypoxia, and the resulting immunosuppression from the combination of these features, posing major challenges in tumor therapy. Although nanozymes have demonstrated remarkable potential in treating malignant tumors, nanozymes with zero-valent metal doping that can simultaneously catalyze the above three indicators to reverse the TME are still limited. Herein, zero-valent ruthenium was anchored on iron-based materials to obtain FeRu nanozymes with ruthenium as the "electron bridge" and iron as the "REDOX center" to enhance the electron transfer efficiency. Its hollow structure significantly exposes more catalytic active sites. Density functional theory calculations theoretically explain the potential triple catalytic and electron transfer mechanisms of the nanozyme. The catalase-like, peroxidase-like, and GSHOx-like activities of FeRu nanozymes rapidly generate a large amount of oxygen and hydroxyl radicals, significantly consume GSH, and disrupt the redox balance in tumor cells. These in situ catalytic reactions lead to cell damage, necrosis in malignant tumors, release of damage-associated molecular patterns, and activation of the adaptive immune response. This work also performs a combined application of anti-programmed cell death-ligand 1 and FeRu nanozymes to further enhance the efficacy of immunotherapy, thus providing a new perspective for future cancer therapy.