Glutathione-responsiveness of copolymer vesicles adjusted by the acid degradation of ketals for enhanced drug-loaded stability and controlled release

Smart block copolymer nanoassemblies are promising drug carriers due to stimuli-responsive degradation-mediated controlled release, yet face challenges balancing drug-loading stability and controlled release. To address this, we developed a dual-responsive system through glutathione (GSH)/pH cascade stimuli. Amphiphilic block copolymers PVP-SeSe-PIMPHMA m (m = 11, 21) were synthesized by linking hydrophilic poly( N -vinylpyrrolidone) (PVP) and hydrophobic poly(isopropylidene-2, 2- bis(methoxy)propionic hydroxyethylmethacrylate) (PIMPHMA) via diselenide bonds. The diselenide bonds and ketal-containing PIMPHMA served as GSH- and pH-responsive motifs, respectively. Self-assembly yielded thermodynamically stable micelles (m = 11) and vesicles (m = 21). PVP-SeSe-PIMPHMA 21 vesicles demonstrated superior doxorubicin (DOX) loading efficiency and stability compared to PVP-SeSe-PIMPHMA 11 micelles. Crucially, vesicles exhibited slow DOX release under individual GSH or pH 6.0 conditions, but accelerated release under combined acidic/GSH stimulation. Mechanistically, acidic degradation of the hydrophobic core reduced vesicle stability while enhancing corona interface reduction, triggering structural dissociation and rapid payload release. The dual-responsive system achieved extended blood circulation with minimized premature leakage, coupled with tumor-specific accumulation through cancer cell GSH overexpression and acidic microenvironment targeting. Cellular studies confirmed efficient uptake, potent cytotoxicity against cancer cells, and favorable biosafety profiles. This cascade-responsive platform resolves the stability-release paradox by synchronizing carrier disintegration with tumor microenvironment triggers, demonstrating significant potential for precision drug delivery through spatiotemporal control of therapeutic release while maintaining systemic stability. • GSH/pH dual responsive copolymer nanoparticles are developed. • Asymmetric Se-Se bond and ketals enable tumor-targeted drug release, preserving system stability. • Doxorubicin-loaded vesicle nanoparticles efficiently enter cells and induce cell death. • GSH/pH dual-responsive vesicle nanoparticles demonstrate excellent blood compatibility and biosafety in vivo .