Fe(III)‐Shikonin Supramolecular Nanomedicine for Combined Therapy of Tumor via Ferroptosis and Necroptosis

Abstract Most of the antitumor chemotherapeutic drugs execute the therapeutic performance upon eliciting tumor cell apoptosis, which may cause chemoresistance of tumors. Design of novel drugs to eradicate apoptosis‐resistant tumors via non‐apoptotic cell death pathways is promising for improving the long‐term chemotherapeutic efficacy. Herein, a Fe(III)‐Shikonin metal‐polyphenol‐coordinated supramolecular nanomedicine for combined therapy of tumor via ferroptosis and necroptosis is designed. The construction of the nanomedicine based on the coordinated self‐assembly between Fe 3+ and Shikonin not only overcomes the shortcomings of Shikonin including its low bioavailability and high toxicity toward normal tissues, but also integrates the theranostics functions of Fe ions. Under the exposure of the high concentration of glutathione (GSH) in tumor cells, the as‐prepared nanomedicine will disassemble into Fe 2+ and Shikonin, followed by stimulating the tumor cell death through ferroptosis and necroptosis. In addition, benefiting from the stealth effect of polyethylene glycol (PEG) and the targeting ability of cyclo(Arg‐Gly‐Asp‐ d ‐Phe‐Lys) (cRGD) to α v β 3 ‐integrin, NH 2 ‐PEG‐cRGD‐modified nanomedicine exhibits a GSH‐responsive therapy toward 4T1 tumor in vivo and self‐enhanced longitudinal relaxation (T 1 )‐weighted imaging property. Since the self‐assembly of natural Shikonin and human body‐necessary Fe element is facile and feasible, the work may provide a promising supramolecular nanomedicine for next‐generation chemotherapeutic applications.