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[Display omitted] • A tumor microenvironment-activated hollow vanadium-based nanoplatform (pLi-HVMSN-Pt) was developed. • pLi-HVMSN-Pt promoted DNA damage via the formation of Pt-DNA adduct and ERCC1 inhibition. • pLi-HVMSN-Pt decreased cellular GSH level via depleting GSH and inhibiting GCL expression. • pLi-HVMSN-Pt enhanced cellular ROS production and then induced cells oxdative death. • pLi-HVMSN-Pt achieved the precise therapy of lung cancer via reversing CDDP resistance. The resistance and side effect of cisplatin (CDDP) were still great challenges for highly efficient therapy of lung cancer in clinic. The studies indicated that the CDDP resistance mainly involved GSH-mediated inactivation and the damaged DNA repair. Herein, a novel vanadium-based nanoplatform was designed via platelet-derived growth factor receptor-β (PDGFR-β)-recognizing cyclic peptide (PDGFB)-labeled liposomes coating onto the hollow vanadium-doped mesoporous silica nanoparticle (HVMSN) loaded Pt (IV) prodrugs (pLi-HVMSN-Pt). This nanoplatform actively targeted tumor tissue, and then effectively responded to weakly acidic and high GSH of tumor microenvironment, making Pt (IV) prodrugs and vanadium ions be precisely delivered and intelligently released. Moreover, the vanadium ions significantly downregulated the expression of glutamyl cysteine ligase (GCL) and excision repair cross-complementing 1 (ERCC1), which inhibited the synthesis of GSH in cells and the damaged DNA repair. These synergistic actions dramatically increased the sensitivity of tumor cells to Pt-based drug, and then reversed CDDP resistance. Furthermore, in vivo experiment results demonstrated highly efficient suppression of tumor growth induced by the pLi-HVMSN-Pt. Therefore, this work provided a novel strategy for reversing CDDP-resistance and the precise therapy of lung cancer. [ABSTRACT FROM AUTHOR]