FeS2-modified MXene nanocomposite platform for efficient PTT/CDT/TDT integration through enhanced GSH consumption

Abstract

Hypoxic microenvironment and glutathione (GSH) accumulation in tumours limit the efficacy of cytotoxic reactive oxygen species (ROS) anti-tumour therapy. To address this challenge, we increased the consumption of GSH and the production of ROS through a novel nanoplatform with the action of inorganic nanoenzymes. In this study, we prepared mesoporous FeS₂ using a simple template method, efficiently loaded AIPH, and assembled Ti₃C₂/FeS₂-AIPH@BSA (TFAB) nanocomposites through self-assembly with BSA and 2D Ti₃C₂. The constructed TFAB nanotherapeutic platform enhanced chemodynamic therapy (CDT) by generating toxic hydroxyl radicals (˙OH) via FeS₂, while consuming GSH to reduce the loss of generated ˙OH via glutathione oxidase-like (GSH-OXD). In addition, TFAB is able to stimulate the decomposition of AIPH under 808 nm laser irradiation to produce oxygen-independent biotoxic alkyl radicals (˙R) for thermodynamic therapy (TDT). In conclusion, TFAB represents an innovative nanoplatform that effectively addresses the limitations of free radical-based treatment strategies. Through the synergistic therapeutic strategy of photothermal therapy (PTT), CDT, and TDT within the tumor microenvironment, TFAB nanoplatforms achieve controlled AIPH release, ROS generation, intracellular GSH consumption, and precise temperature elevation, resulting in enhanced intracellular oxidative stress, significant apoptotic cell death, and notable tumor growth inhibition. This comprehensive treatment strategy shows great promise in the field of tumor therapy.