A ferroptosis-inducing biomimetic nanocomposite for the treatment of drug-resistant prostate cancer

Second-generation androgen receptor (AR) inhibitors such as enzalutamide are the first-line treatments for castration-resistant prostate cancer (CRPC). Resistance to enzalutamide will greatly increase the difficulty of prostate cancer treatment and reduce the survival time of patients. However, drug-resistant cancer cells seem to be more sensitive to ferroptosis. Therefore, we constructed a biomimetic tumor-targeting magnetic lipid nanoparticle (t-ML) to codeliver dihomo-γ-linolenic acid (DGLA) and 2,4-dienoyl-CoA reductase 1 (DECR1) siRNA (t-ML@DGLA/siDECR1). DGLA is a dietary polyunsaturated fatty acid (PUFA), while DECR1 is overexpressed in prostate cancer and can inhibit the generation of PUFAs. The combination of DGLA and siDECR1 can efficiently induce ferroptosis by peroxidation of PUFAs, which has been verified both in vitro and in vivo. With the assistance of an external magnet, t-ML showed good tumor targeting ability and biocompatibility, and t-ML@DGLA/siDECR1 exhibited significant ferroptosis induction and tumor suppression capabilities. Moreover, in a nude mouse model of prostate cancer fed on a high-fat diet (HFD), there was no distant organ metastasis when the tumor-bearing mice were treated with t-ML@DGLA/siDECR1 and an external magnet, with upregulated PUFAs and downregulated monounsaturated fatty acids (MUFAs). Hence, this study has broadened the way of treating drug-resistant prostate cancer based on ferroptosis induction.