Tuning band gap of MnO2 nanoflowers by Alkali metal doping for enhanced Ferroptosis/phototherapy synergism in Cancer

Due to the complexity and heterogeneity of tumors, the therapeutic effectiveness of monomodal phototherapy is still limited. As aggressive tumors become more vulnerable to ferroptosis, synergistic ferroptosis/phototherapy has recently emerged as a promising noninvasive anti-cancer strategy. However, desirable phototherapeutic materials exhibiting altogether the required properties including excellent photothermal/photocatalytic performance, long-term biosafety and ferroptosis-inducing capability remains challenging. Herein, the present study proposed a novel strategy to construct a multifunctional nanoplatform based on band gap engineering of semiconductor nanomaterials for synergistic phototherapy. Specifically, a novel alkali-metal doped δ-MnO2 nanoflower with tunable band gap and controllable degradability was developed to realize a highly efficient and safe synergistic ferroptosis/photothermal/photocatalytic therapy. The desirable near-infrared light (NIR)-excited photothermal/photocatalytic properties of MnO2 nanoflowers were endowed and enhanced by narrowing band gap via increasing the doping alkali metal ionic radius (Mg2+<Na+<K+). Such synergistic photothermal/photocatalytic actions further band gap dependently improved anti-tumor phototherapeutic efficacy by triggering ferroptosis in tumor cells with the increase of redox-active iron (Fe2+), the accumulation of lipid peroxidation (LPO) and the downregulation of glutathione peroxidase 4 (GPX4), and thereby achieving nearly complete tumor elimination with a high tumor inhibition efficiency (98.8%) in vivo. Following the injection of Vitamin C, the MnO2 nanoflowers were almost completely degraded into manganese (Mn) ions and rapidly excreted from the body, making this approach attractive for in vivo applications. Our findings pave the way to manipulate structural characteristics of semiconductor nanomaterials to practice novel therapeutic properties, and provides important insights towards the rational design and understanding of phototherapeutic materials.