Enhanced Ferroptosis by Oxygen-Boosted Phototherapy Based on a 2‑in‑1 Nanoplatform of Ferrous Hemoglobin for Tumor Synergistic Therapy

Photodynamic therapy (PDT) combined with oxygenating strategies is widely employed in cancer treatment; however, oxygen-boosted PDT has failed to achieve an ideal effect due to the complexity, heterogeneity, and irreversible hypoxic environment generated by tumor tissues. With the emergence of Fe-dependent ferroptosis boasting reactive oxygen species (ROS) cytotoxicity as well, such a chemodynamic approach to cancer therapy has drawn extensive attention. In this study, hemoglobin (Hb) is connected with the photosensitizer chlorin e6 (Ce6) to construct a 2-in-1 nanoplatform (SRF@Hb-Ce6) with Sorafenib (SRF, ferroptosis promotor) loaded, combining oxygen-boosted PDT and potent ferroptosis. Benefiting from the intrinsic presence of Fe capable of binding oxygen, hemoglobin concurrently furnishes oxygen for oxygen-dependent PDT and Fe for Fe-dependent ferroptosis. Furthermore, amphiphilic MMP2-responsive peptide is incorporated into the skeleton of the nanoplatform to ensure drug-release specificity for safety improvement. Correlative measurements demonstrate the potentiation of PDT and ferroptosis with SRF@Hb-Ce6. More importantly, PDT strengthens ferroptosis by recruiting immune cells to secrete IFN-γ, which can sensitize the tumor to ferroptosis in our findings. The therapeutic effect of synergistic treatment with SRF@Hb-Ce6 in vitro and in vivo was proven significant, revealing the promising prospects of combined PDT and ferroptosis therapy with the 2-in-1 nanoplatform.