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.