Multifunctional porphyrinic metal-organic framework-based nanoplatform regulating reactive oxygen species achieves efficient imaging-guided cascaded nanocatalytic therapy.

The integration of reactive oxygen species (ROS) related photodynamic therapy (PDT) with the strategy of reshaping the tumor microenvironment (TME) has emerged as a potential approach for nanodiagnostic and therapeutic interventions. However, the therapeutic efficacy based on ROS treatments may be hindered by intracellular antioxidants such as glutathione (GSH) and tumor hypoxia. To address these challenges, a nanoplatform based on GSH-responsive multifunctional porphyrinic metal-organic framework (PCN-224@Au@MnO2@HA, PAMH) was proposed. It was developed through a layer-by-layer in-situ growth method. This method avoids the need for high-temperature calcination and complex modification processes while improving the stability of PCN-224 in a phosphate-rich environment. GSH depletion leads to oxidation-reduction imbalance in TME. With the inactivation of GSH peroxidase 4 (GPX4), the content of hydrogen peroxide (H2O2) increases, ultimately triggering lipid peroxidation (LPO) and promoting ferroptosis. The catalase-like activity of Au nanozymes facilitates the generation of oxygen (O2), thereby mitigating tumor hypoxia and downregulating hypoxia-inducing factors (HIF-1α). Due to the presence of porphyrin ligands in PCN-224, the generated O2 can be further converted to toxic singlet oxygen (1O2) under laser irradiation. Additionally, the platform allows near-infrared (NIR) fluorescence imaging, providing real-time information on intracellular GSH changes during PDT and ferroptosis. The PAMH nanoplatform has shown effective inhibition of tumor growth in subcutaneous models via both intravenous and intratumoral injection, indicating its potential in modulating reactive oxygen/sulfur species and reshaping TME, thereby facilitating imaging-guided cascaded nanocatalytic therapy.