Hijacking the hyaluronan assisted iron endocytosis to promote the ferroptosis in anticancer photodynamic therapy

Photodynamic therapy (PDT) eradicates tumor cells by the light-stimulated reactive oxygen species, which also induces lipid peroxidation (LPO) and subsequently ferroptosis, an iron-depended cell death. Ferroptosis has a tremendous therapeutic potential in cancer treatment, however, the ferroptosis efficiency is largely limited by the available iron in cells. Through hijacking the CD44-mediated iron endocytosis of hyaluronan (HA), here PDT with enhanced ferroptosis was realized by a HA@Ce6 nanogel self-assembled from HA, a photosensitizer Chlorin e6 (Ce6) and Fe³⁺ as cross-linkers. Taking advantages of HA's natural affinity towards CD44, HA@Ce6 enabled a targeted Ce6 delivery in CD44-overexpressed breast cancer cells and meanwhile enhanced iron uptake to “fuel” ferroptosis together with the light-stimulated LPO. Further, HA@Ce6 demonstrated an excellent anticancer PDT efficacy and ferroptosis induction in the murine 4 T1 xenograft model. This HA@Ce6 successfully exploited the role of HA in iron transport to sensitize ferroptosis, providing a potent strategy to facilitate the anticancer PDT.