Photoactivatable metal organic framework for synergistic ferroptosis and photodynamic therapy using 450 nm laser

Photodynamic therapy (PDT) is an appealing treatment modality by producing reactive oxygen species (ROS) with photosensitizers (PSs) to induce cell apoptosis, but still suffering poor efficacy in treating hypoxic solid tumor. Herein, we have developed a nanocarrier (naming HAFeR) by encapsulating PSs and RSL3 in metal organic framework (MOF) for synergistic ferroptosis and PDT. HAFeR nanocarriers selectively recognized CD44 overexpressed on tumor cell surface, and were subsequently internalized via receptor mediated endocytosis. After transferring inside acidic lysosomes, nanocarriers were decomposed to release the payloads, including porphyrin sensitizers, Fe²⁺, Fe³⁺ and RSL3. Under 450 nm laser irradiation, the porphyrin produced more massive ROS to induce drastic cell apoptosis than 630 nm laser due to higher photon energy and stronger absorption. Meanwhile, exogenous iron ions catalyzed the conversion of H₂O₂ into O₂ to alleviate tumor hypoxia via Fenton reaction, and also promoted RSL3 to downregulate GPX4 to induce lipid peroxidation (LPO), finally boosting ROS production for ferroptosis. By combining apoptosis and ferroptosis, HAFeR showed potent toxicity to tumor cells and efficiently eradicated the tumor in MB49 tumor-bearing nude mice under 450 nm laser, providing a potential strategy combining laser ablation and PDT within one system for future intraluminal and superficial tumor treatment.