Biodegradable Dual-Responsive Polycarbonate Nanoplatform for Synergistic Platinum Sensitization via Glutathione Depletion and Oxidative Stress Amplification

Platinum-based chemotherapeutics remain fundamental in cancer treatment but are limited by poor tumor selectivity, rapid systemic clearance, and drug inactivation mediated by elevated intracellular glutathione (GSH). To address these limitations, we developed an amphiphilic polycarbonate nanoplatform (PCN) to codeliver cinnamaldehyde (CA), nitric oxide (NO), and a GSH-activatable Pt(IV) prodrug (PtBr). In this system, CA was conjugated to polycarbonate (mPEG–PCO) via acid-labile acetal bonds for pH-responsive release, while nitrate-functionalized polycarbonate (mPEG–PMNC) enabled GSH-triggered NO generation. The resulting nanomicelles (PCN@PtBr) facilitated efficient tumor cell uptake and synchronized release of therapeutic components within the tumor microenvironment. Mechanistically, CA enhanced intracellular ROS production, whereas NO generation and PtBr activation cooperatively depleted GSH, thereby disrupting the antioxidant defense of tumor cells. The reaction between NO and ROS further produced highly cytotoxic peroxynitrite (ONOO–), amplifying oxidative and nitrosative stress. This cascade triggered mitochondrial dysfunction and severe DNA damage, ultimately inducing apoptosis in tumor cells via apoptosis-related pathways. In a 4T1 orthotopic breast cancer model, PCN@PtBr exhibited pronounced tumor accumulation and potent tumor growth inhibition (∼84.8%) with favorable biosafety. Overall, this work provides an effective nanotherapeutic strategy to enhance platinum chemotherapy by amplifying redox imbalance and dismantling tumor antioxidant defenses.