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.