A metal-phenolic network-assembled nanotrigger evokes lethal ferroptosis via self-supply loop-based cytotoxic reactions

The therapeutic efficacy of photodynamic therapy (PDT) is compromised by the hypoxic tumor microenvironment, while the ferroptosis therapy suffers from a lack of selectivity. Herein, the photosensitizer chlorin e6 (Ce6)-loaded hemoglobin (Hb) is assembled with the metal–phenolic network (MPN) formed by ferric ions (Fe3+) and tannic acid (TA), to construct a nanotrigger Hb–Ce6–Fe3+–TA (HCFT) for the combination of oxygen self-supply PDT and light-triggered ferroptosis therapy. Benefiting from the oxygen-carrying ability of Hb, the nanotrigger can relieve the tumor hypoxia and induce enhanced photodynamic reaction, resulting in the increase of intracellular reactive oxygen species (including H2O2) level. Furthermore, the elevated H2O2 level facilitates the continuation of the MPN-mediated Fe2+ self-supply Fenton reaction and thereby causes excessive cellular lipid peroxidation, which ultimately leads to lethal ferroptosis in tumor cells. Under laser irradiation, HCFT shows satisfactory antitumor effect due to the synergistic amplification of oxidative stress induced by photodynamic reaction and enhanced Fenton reaction. By comparison, without light illumination, the HCFT nanotrigger exhibits negligible cytotoxicity, indicating its light-controlled lethality. This study may have implications for the future development of efficacious oxidative stress-based synergistic therapeutic strategies that may possibly lead to successful clinical translation.