Nanozyme-based chemodynamic therapy (CDT) has shown tremendous potential in the treatment of bacterial infections. However, the CDT antibacterial efficacy is severely limited by the catalytic activity of nanozymes or the infection microenvironments such as insufficient hydrogen peroxide (HO) and overexpressed glutathione (GSH). Herein, a versatile hybrid nanozyme (MoS/CuO) is rationally constructed by simply decorating ultrasmall CuO nanodots onto lamellar MoS platelets of hydrangea-like MoS nanocarrier via a covalent Cu-S bond. The MoS/CuO nanozyme exhibits the peroxidase-mimic activity for catalytically converting HO produced by acid-triggered decomposition of the decorated CuO into hydroxyl radical (•OH). Meanwhile, the MoS/CuO can consume GSH overexpressed in the infection sites via redox reaction mediated by polyvalent transition metal ions (Cu and Mo) for enhanced CDT. More importantly, MoS support can promote the conversion of Cu to Cu by a co-catalytic reaction based on the Mo/Mo redox couples, and provide photonic hyperthermia (PTT) to augment the peroxidase-mimic activity. The developed MoS/CuO nanozymes possesses a desirable catalytic property, as well as a remarkably improved antibacterial efficiency both in vitro and in vivo. Taken together, this study proposes a synergetic multiple enhancement strategy to successfully construct the versatile hybrid nanozymes for intensive in vivo PTT/CDT dual-mode anti-infective therapy. STATEMENT OF SIGNIFICANCE: Chemodynamic therapy (CDT) has shown great potentialities in the treatment of bacterial infections, while its therapeutic efficiency is severely limited by the infection microenvironments such as insufficient hydrogen peroxide (HO) and overexpressed glutathione (GSH). Here, we rationally construct a hybrid nanozyme (MoS/CuO) with peroxidase-like activity that can enhance CDT by regulating local microenvironments, that is, simultaneously self-supplying HO and consuming GSH. Importantly, MoS support can promote the conversion of Cu to Cu by the Mo/Mo redox couples, and provide photonic hyperthermia (PTT) to augment the peroxidase-mimic activity. The developed MoS/CuO shows desirable PTT/CDT dual-mode antibacterial efficacy both in vitro and in vivo. This study proposes a versatile hybrid nanozyme with multiple enhancement effects for intensive in vivo anti-infective therapy.