Gold Nanoparticles Functionalized with Au–Se-Bonded Peptides Used as Gatekeepers for the Off-Target Release of Resveratrol in the Treatment of Triple-Negative Breast Cancer

Resveratrol has been garnering considerable attention as a promising chemopreventive and chemotherapeutic drug against metastatic tumors such as triple-negative breast cancer (TNBC). However, the potential in vivo application of resveratrol has been highly limited due to its poor solubility, rapid conjugation, low bioavailability, and bioactivity. In this study, a silica mesoporous nanoparticle (MSN)-based drug delivery system (DDS), named Au-Se@MSN, is developed to deliver the loaded resveratrol, endowing it with properties of targeted delivery, excellent bioavailability, and antioxidation of resveratrol. In Au-Se@MSN(RES), gold nanoparticles functionalized with selenol-modified uPA-specific peptides act as gatekeepers to avoid the interference of glutathione in the bloodstream and realize negligible premature release of resveratrol during delivery. Au-Se@MSN(RES) shows prolonged resveratrol release at the tumor site and endows resveratrol with a remarkable in vitro therapeutic effect. The pharmacological dose of resveratrol treatment on MDA-MB-231 cells was found to result in the generation of a high level of NAD(P)H other than H₂O₂, indicating reductive stress instead of oxidative stress involved in the resveratrol therapeutic process. In vivo experiments showed that Au-Se@MSN greatly improves the chemotherapeutic effect of resveratrol on mice bearing TNBC tumors, and damage to normal tissues and cells is negligible. Overall, Au-Se@MSN is a potential tool for further studies on the anticancer mechanism and clinical applications of resveratrol.