A Self-Amplifying Nanodrug to Manipulate Janus-Confronted Nature of Ferroptosis for Tumor Remedy

Ferroptosis, an uncommon nonapoptotic cell dying attributable to iron-dependent accumulation of lipid peroxide, allows versatile design of antitumor platform. Particularly, as a optimistic position, ferroptosis can induce immune response accompanied with the interferon-γ (IFN-γ)-triggered disruption of the glutathione peroxidase 4 pathway for cascade enhancement of ferroptotic cell dying and ferroptosis-induced immunotherapeutic efficacy. Nonetheless, as a unfavorable position, ferroptosis additionally triggers inflammation-associated immunosuppression by up-regulation of cyclooxygenase-2/prostaglandin E2 pathway and IFN-γ-associated adaptive immune resistance by up-regulation of programmed dying ligand-1 (PD-L1), impeding the antitumor efficacy of a number of immune cells by immune escape. Detrimental and optimistic roles endow ferroptosis with janus-faced nature. It’s pressing to control the janus-faced nature of ferroptosis for eliciting the maximized ferroptotic therapeutic efficacy. Herein, a self-amplifying nanodrug (RCH NPs) was designed by co-assembling hemin (ferric porphyrin), celecoxib (anti-inflammatory drug) and roscovitine (cyclin-dependent kinase 5 inhibitor) with the help of human serum albumin for reprograming janus-faced nature of ferroptosis. Throughout hemin-triggered ferroptosis, celecoxib disrupted the inflammation-related immunosuppression whereas roscovitine destroyed IFN-γ-induced up-regulation of PD-L1 by genetic blockade impact. The RCH NPs thus demonstrated superior therapeutic results on tumors, because of the self-amplifying ferroptotic immunotherapy. Our work presents a conceptually modern technique for harnessing ferroptosis towards tumors.