Ti₂C(OH)₂‑MXene Nanosheets To Salvage Critical Limb Ischemia by Catalyzing the Generation of Oxygen from Endogenous Hydrogen Peroxide

Overproduction of reactive oxygen species accompanied by hypoxia and inflammation in critical limb ischemia contributes to aggravated limb gangrene and loss. However, the existing drug and surgical treatments are not satisfactory. Nanoenzymes that catalyze endogenous H₂O₂ into O₂ to reshape the hostile oxidative microenvironment are a promising strategy for increasing limb salvage rates. Here, Ti₂C(OH)₂-MXene nanosheets were prepared and used for the treatment of limb ischemia. The biological activity and therapeutic effects of the nanosheets were verified in vitro using HUVECs and 3T3 cells, and in vivo using a C57BL/6 mouse model of femoral arteriovenous resection. Results showed that the nanosheets catalyze H₂O₂ into O₂ in a gentle and sustainable manner. Notably, they exhibit a strong protective effect on cell viability and motility and regulate the intracellular levels of ROS and O₂ under inflammatory conditions. More importantly, when delivered to ischemic hindlimbs in mice, the nanosheets inhibited in vivo ROS accumulation, promoted macrophage polarization from M1 to M2 to reduce inflammation, and upregulated the expression of myogenic regulatory factors (MyoG and MyoD) to protect skeletal muscle from necrosis. Over a 21-day monitoring period, significantly enhanced angiogenesis and limb salvage were observed. Together, our results indicate that Ti₂C(OH)₂ nanosheets are a type of nanoenzyme that may effectively treat critical limb ischemia.