Nanoscale “precision strike”: Tumor microenvironment-responsive smart micelles for efficient targeted drug delivery

To address the limitations of conventional nanotechnology-based drug delivery systems, this work developed enzyme and reduction dual-responsive polymeric micelles. These micelles were synthesized with copolymers composed of TPGS3350-PVGLIG-DOX (TPD) and FA-SS-DOX (FSD), which endow them with tumor-targeted drug delivery capabilities. TPGS3350 contributes to extending the circulation of micelles in body, augmenting their accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect. Upon localized the tumor site, matrix metalloproteinase 2 (MMP2) cleaves the PVGLIG peptide moiety within the micelles, thereby releasing TPGS3350 and exposing the targeting ligand of folate. This approach enables the subsequent internalization of the micelles by tumor cells through folate receptor-mediated endocytosis. After internalization, the high intracellular concentration of glutathione (GSH) triggers the reduction of the disulfide bond within the FA-SS-DOX, leading to the release of the anticancer-drug doxorubicin (DOX), which promotes apoptosis in the tumor cells and enhances the efficacy of chemotherapy.