Daidzein-engineered high-accumulation self-therapeutic nanoplatform drives androgen receptor degradation via ubiquitination-proteasome system to overcome enzalutamide resistance in castration-resistant prostate cancer

High levels of androgen receptor (AR) are associated with poor prognosis and drug resistance in castration-resistant prostate cancer (CRPC), and monotherapy with AR antagonists such as enzalutamide (Enz) is currently inadequate to meet the clinical needs. Dual-targeted therapeutic strategy of AR degradation combined with AR inhibition is a promising strategy to improve the efficacy and to address the problem of drug resistance in CRPC, thus the development of safer, stable, and effective agents with AR-degrading activity is urgent. In our study, we found that daidzein, a phytoestrogen, could reduce the risk of prostate cancer, exhibited a good affinity for AR and down-regulated AR levels. Consequently, we developed daidzein-based, redox-responsive self-therapeutic nanocarriers to deliver Enz (D44DA@Enz NPs) to realize the dual-targeted therapeutic strategy against AR in CRPC. The results showed that D44DA NPs facilitated AR degradation via the ubiquitin-proteasome pathway, which combined with the inhibitory effect of Enz on AR nuclear translocation greatly improved the efficacy against CRPC. <i>In vivo</i> studies, D44DA NPs demonstrated approximately 40-fold increased enrichment at the tumor site, exhibited excellent self-antitumor activity and synergistically enhanced the therapeutic effects of Enz with minimal toxic side effects. In summary, this study provides a highly promising AR-degrading active nanoplatform and dual-targeted AR therapeutic strategy for the treatment of CRPC.