In situ oxygen-producing nanoplatform inducing multifunctional cell death for enhanced photodynamic therapy of hypoxic tumors

The apoptosis induced by photodynamic therapy (PDT) is often restricted by the hypoxic state of the tumor microenvironment (TME). Additionally, tumor cells exhibit acquired and intrinsic resistance to apoptosis, further limiting the effectiveness of apoptosis. Here, an advanced nanoplatform Fe/CuO2@FA, which enhanced the PDT effect through inducing multifunction cell death was proposed. Under near-infrared laser (NIR), the PDT effect of Fe/CuO2@FA was activated to generate reactive oxygen species (ROS) and trigger apoptosis. Beneath acidic microenvironment, Fe/CuO2@FA released CuO2 nanodots, and then decomposed to produce O2, mitigating the hypoxic state of TME and further enhancing the PDT effect. Fe3+ and Cu2+ in Fe/CuO2@FA down-regulated the expression of glutathione peroxidase 4 (GPX4) and caused lipid peroxide (LPO) through depleting glutathione (GSH) and generating hydroxyl radicals (center dot OH), triggering ferroptosis. The increase of iron concentration further enhanced the sensitivity of ferroptosis and accelerated cell death. The excellent in vivo imaging systems (IVIS) imaging ability of Fe/CuO2@FA allowed real-time monitoring of enrichment of nanoparticles and tumor progression. This multimodal cell death strategy of self-supplied O2 provides a novel perspective for reinforcing the anti-tumor efficacy of PDT, which is expected to become an efficient method for tumor treatment.