Surface Charge-Modulated Biomimetic Core-Shell Hybrid Nanovesicles for Redox-Triggered Synergistic Cancer Therapy

Despite the therapeutic potential of photodynamic therapy (PDT), its clinical efficacy is frequently limited by insufficient photosensitizer (PS) delivery and the strong antioxidant defense mechanisms of tumor cells. In this study, we developed surface charge-modulated biomimetic core-shell nanostructures by encapsulating PS-loaded poly(benzene-1,4-dithiol) (pBDT) nanoparticles within cell-derived nanovesicles (CNVs). To address the electrostatic barriers associated with tumor tissues, the CNV shell was functionalized with a controlled amount of cationic lipids (1,2-dioleoyl-3-trimethylammonium-propane, DOTAP). This modification was designed to modulate surface electrostatic interactions at the tumor interface while maintaining membrane integrity and systemic safety. The resulting hybrid nanovesicles, termed PS/pBDT@cCNVs, integrate the redox-responsive properties of the pBDT core with the intrinsic biological functionalities of the CNV shell. This dual-modal strategy, which combines surface charge modulation with the intrinsic biological properties of CNVs, led to enhanced tumor accumulation and improved intratumoral distribution. Furthermore, the redox-active PS/pBDT core facilitated efficient intracellular ROS generation and glutathione (GSH) depletion, thereby amplifying the phototherapeutic impact. Both in vitro and in vivo evaluations confirmed that PS/pBDT@cCNVs achieved robust tumor ablation with negligible systemic toxicity. Collectively, this work presents a rationally designed, charge-tunable, redox-responsive hybrid nanoplatform that addresses key biological barriers in photodynamic cancer therapy.