GSH-induced chemotaxis nanomotors for cancer treatment by ferroptosis strategy

Overexpression of glutathione (GSH) in tumor cells greatly inhibits the therapy effect of traditional ferroptosis inducers; thus, control of the GSH level is an important way to improve the efficacy of ferroptosis. Herein, a kind of nanomotor based on metal organic framework material NH2-MIL-101 is constructed, in which polyethylene glycol (PEG) and glutathione hydrolase γ-glutamyltransferase (GGT) are asymmetrically modified to obtain mPEG@MIL-101@GGT nanomotors (PMG NMs). The nanomotor proposed in this article can be induced by overexpressing GSH in tumors to form chemotactic effects through the specific affinity between enzymes and substrates. Results indicate that the tail structure provided by PEG and the affinity between GGT and GSH can enable the stable chemotaxis behavior of nanomotors in a complex environment, thus enriching and penetrating deeply at the tumor site. In addition, after loading the ferroptosis inducer Erastin, the system shows a highly effective induction effect of tumor ferroptosis. Erastin in the system can effectively inhibit the synthesis of GSH, and PMG NMS can react with GSH through Fe3+ and GGT to promote GSH depletion. The produced Fe2+ can generate excessive reactive oxygen species through Fenton reaction, which further promotes the death of tumor cells. Meantime, the chemotaxis behavior of the nanomotors based on the endogenous biochemical reaction of GGT-catalyzed GSH hydrolysis can endow nanomotors with the enhanced delivery and penetration ability in tumors, thus collaboratively enhancing the ferroptosis effect. This strategy designed according to the physiological characteristics of tumors has good biosafety and treatment effect, providing new perspectives for micro/nanomotor and tumor treatment.