Dual enzyme-driven redox homeostasis disruption with ultrasmall Pt-decorated MoS2 for combined ferroptosis therapy of hepatocellular carcinoma

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 <i>in vitro</i> and <i>in vivo</i> 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.