Nanoparticle Composites Comprised of Hyaluronic Acid-Decorated Metal–Organic Frameworks with Encapsulated l-Buthionine Sulfoximine and Chlorin e6 for Chemodynamic/Photodynamic Synergistic Cancer Therapy

Reactive oxygen species (ROS) mediated cancer therapy has attracted tremendous interest. Nevertheless, the overexpression of intratumoral glutathione (GSH) reduced the oxidative stress and suppressed the efficiency of ROS-based dynamic anticancer treatment. Herein, a degradable nanocomposite, Fe(SS)-MOF@BSO/Ce6@HA (FMBCH), was developed based on a hyaluronic acid-decorated metal–organic framework with encapsulated l-buthionine sulfoximine (BSO) and chlorin e6 (Ce6) for enhanced PDT and CDT. Once accumulated at the tumor region, the original GSH would be depleted via the redox reaction between GSH and S–S bonds and Fe3+ in FMBCH, leading to the decomposition of the nanoplatform and release of Fe2+, Ce6, and BSO. Fe2+ would catalyze endogenous H2O2 to lethal hydroxyl radicals (•OH), and Ce6 would convert oxygen to 1O2 under irradiation, inducing the death of cancer cells via the cooperation of CDT and PDT. Furthermore, BSO could suppress the GSH biosynthesis and downregulate glutathione peroxidase 4 (GPX4) expression, resulting in the excessive accumulation of lipid peroxidation (LPO). The in vitro and in vivo studies demonstrated that FMBCH could promote the therapeutic effect of CDT and PDT benefiting from its excellent multistage GSH depletion property. The engineered nanosystem provided a promising strategy for improving ROS-based antitumor efficiency via integrating the dual GSH elimination approach.