Developing Single-Atomic Manganese Nanozymes for Synergistic Mild Photothermal/Multienzymatic Therapy

Synergistic mild photothermal/nanozyme therapy with outstanding hyperthermia performance and excellent multienzyme properties is highly needed for osteosarcoma treatment. Herein, we have developed efficient single-atom nanozymes (SANs) consisting of Mn sites atomically dispersed on nitrogen-doped carbon nanosheets (denoted as Mn-SANs) for synergistic mild photothermal/multienzymatic therapy against osteosarcoma. Benefiting from their black N-doped carbon nanosheet matrices, Mn-SANs showed an excellent NIR-II-triggered photothermal effect. On the other hand, Mn-SANs with atomically dispersed Mn sites have outstanding multienzyme activities. Mn-SANs can catalyze endogenous H₂O₂ in osteosarcoma into O₂ by catalase (CAT)-like activity, which can effectively ease osteosarcoma hypoxia and trigger the oxidase (OXD)-like catalysis that converts O₂ to the cytotoxic superoxide anion radical (^•O₂^-). At the same time, Mn-SANs can also mimic glutathione oxidase (GSHOx) to effectively consume the antioxidant glutathione (GSH) in osteosarcoma and inhibit intracellular glutathione peroxidase 4 (GPX4) expression. Such intratumoral ^•O₂^- production, GSH depletion, and GPX4 inactivation mediated by Mn-SANs can create a large accumulation of lipid peroxides (LPO) and ^•O₂^-, leading to oxidative stress and disrupting the redox homeostasis in osteosarcoma cells, which can ultimately induce osteosarcoma cell death. More importantly, heat shock proteins (HSPs) can be significantly destroyed via Mn-SAN-mediated plentiful LPO and ^•O₂^- generation, thus effectively impairing osteosarcoma cells resistant to mild photothermal therapy. Overall, through the cooperative effect of chemical processes (boosting ^•O₂^-, consuming GSH, and enhancing LPO) and biological processes (inactivating GPX4 and hindering HSPs), collaborative mild photothermal/multienzymatic therapy mediated by Mn-SANs is a promising strategy for efficient osteosarcoma treatment.