Engineering nanoenzymes integrating Iron-based metal organic frameworks with Pt nanoparticles for enhanced Photodynamic-Ferroptosis therapy

Photodynamic therapy (PDT), as a promising strategy in cancer treatment that utilizes photosensitizers (PSs) to produce reactive oxygen species, has been widely used for eliminating cancer cells under specific wavelength light irradiation. However, the low aqueous solubility of PSs and special tumor microenvironments (TME), such as high glutathione (GSH) and tumor hypoxia remain challenges towards PDT for hypoxic tumor treatment. To address these problems, we constructed a novel nanoenzyme for enhanced PDT-ferroptosis therapy by integrating small Pt nanoparticles (Pt NPs) and near-infrared photosensitizer CyI into iron-based metal organic frameworks (MOFs). In addition, hyaluronic acid was adhered to the surface of the nanoenzymes to enhance the targeting ability. In this design, MOFs act not only as a delivery vector for PSs, but also a ferroptosis inducer. Pt NPs stabilized by MOFs were functioned as an oxygen (O 2 ) generator by catalyzing hydrogen peroxide into O 2 to relieve tumor hypoxia and increase singlet oxygen generation. In vitro and in vivo results demonstrated that under laser irradiation, this nanoenzyme could effectively relive the tumor hypoxia and decrease the level of GSH, resulting in enhanced PDT-ferroptosis therapy against hypoxic tumor. The proposed nanoenzymes represent an important advance in altering TME for improved clinical PDT-ferroptosis therapy, as well as their potential as effective theranostic agents for hypoxic tumors.