| Summary: | There is an urgent clinical task for developing novel and precise therapies to enhance the treatment efficiency of hepatocellular carcinoma (HCC). Ferroptosis, a form of non-apoptotic regulated cell death, plays a significant role in improving cancer treatment outcomes. However, the robust antioxidant defense system within the tumor microenvironment (TME) severely impacts the ferroptosis efficacy. Nanozymes are emerging as promising candidates for inducing ferroptosis, but constructing novel nanozymes with high catalytic efficiency and multiple activities to amplify ferroptosis's therapeutic effects remains challenging. Here, we have judiciously fabricated a bimetallic nanozyme of ultrasmall Pt-decorated MoS2 (Pt@MoS2) through a simple and efficient aqueous synthesis strategy. The doping of ultrasmall Pt nanoparticles significantly enhances the photothermal activity, peroxidase-like activity, and glutathione oxidase-like activity of MoS2. Under the weak acidic conditions, over-expressed hydrogen peroxide (H2O2), and high glutathione (GSH) levels, Pt@MoS2 nanozyme with dual enzyme-driven redox homeostasis disruption can be activated to break down the antioxidant defense system and reshape the TME, effectively causing ·OH production from H2O2 and GSH consumption. The dual nanozyme-remodulated TME suffers from oxidative cellular damage and significantly accelerates HCC apoptosis and ferroptosis. Both in vitro and in vivo experimental results demonstrate that Pt@MoS2 has successfully induced cancer cell oxidative damage, lipid peroxidation, and downregulation of glutathione peroxidase 4 expression under near-infrared (NIR) laser-assisted photothermal therapy, exhibiting remarkable antitumor efficacy and good biosafety. This study offers insights into designing efficient bimetallic nanozymes for enhanced TME reshaping and ferroptosis therapy and expanding nanozymes' application in cancer treatment.
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