Oxygen-boosted biomimetic nanoplatform for synergetic phototherapy/ferroptosis activation and reversal of immune-suppressed tumor microenvironment

Photodynamic therapy (PDT) induces Apoptosis of Cancer cells by generating cytotoxic Reactive Oxygen Species, the therapeutic effect of which, however, is impeded by intrinsic/inducible apoptosis-resistant mechanisms in Cancer cells and hypoxia of tumor microenvironment (TME); also, PDT-induced anti-tumor immunity activation is insufficient. To deal with these obstacles, a novel biomimetic nanoplatform is fabricated for the precise delivery of photosensitizer chlorin e6 (Ce6), hemin and PEP20 (CD47 inhibitory peptide), integrating oxygen-boosted PDT, Ferroptosis activation and CD47-SIRPα blockade. Hemin's catalase-mimetic activity alleviates TME hypoxia and enhances PDT. The nanoplatform activates Ferroptosis via both classical (down-regulating Glutathione Peroxidase 4 pathway) and non-classical (inducing Fe²⁺ overload) modes. Besides the role of hemin in consuming glutathione and up-regulating heme oxygenase-1 expression, interestingly, we observe that Ce6 enhance Ferroptosis activation via both classical and non-classical modes. The anti-cancer immunity is reinforced by combining PEP20-mediated CD47-SIRPα blockade and PDT-mediated T cell activation, efficiently suppressing primary tumor growth and metastasis. PEP20 has been revealed for the first time to sensitize Ferroptosis by down-regulating system Xc^-. This work sheds new LIGHT on the mechanisms of PDT-ferroptosis activation interplay and bridges immunotherapy and Ferroptosis activation, laying the theoretical foundation for novel combinational modes of Cancer treatment.

CD47-SIRPα blockade; Chlorin e6 (Ce6); Ferroptosis; Hemin; Photodynamic therapy (PDT).