GSH-Responsive Co-Delivery of Chrysin and 3-Methyladenine Disrupts Tumor Adaptive Stress for Synergistic Antitumor Therapy

Cancer remains a major global health challenge, and conventional therapies are still limited by poor tumor specificity, therapeutic resistance, and systemic side effects. Herein, we developed a glutathione (GSH)-responsive FFSSFF coacervate system for the codelivery of chrysin (CH) and the autophagy inhibitor 3-methyladenine (3-MA) to induce tumor-selective autophagic stress. CH activated endoplasmic reticulum stress and promoted autophagy through the GRP78/PERK and Akt/mTOR signaling pathways, while 3-MA simultaneously disrupted autophagic flux, leading to intracellular homeostasis imbalance, mitochondrial dysfunction, excessive reactive oxygen species accumulation, and tumor cell death. The resulting CH/3-MA@FFSSFF coacervates exhibited favorable physicochemical properties, GSH-responsive behavior, efficient intracellular uptake, and selective accumulation in tumor cells. Both in vitro and in vivo experiments demonstrated potent antitumor activity of the CH/3-MA@FFSSFF system. In particular, in an orthotopic lung cancer model, CH/3-MA@FFSSFF effectively suppressed tumor growth, prolonged median survival time, and inhibited tumor cell migration and invasion. Collectively, this study presents a promising liquid–liquid phase separation-derived coacervate platform for targeted combinational cancer therapy through the induction of autophagic stress, with enhanced therapeutic efficacy and reduced off-target toxicity.