Carrier-as-Prodrug Glycyrrhizic Acid Nanogel Co-Delivers Mannose and Glycyrrhetinic Acid for Metabolic-Ionic Cancer Therapy.

Cancer cells evade conventional therapies by dynamically switching between glycolysis and oxidative phosphorylation (OXPHOS). Simultaneous blockade of both pathways could overcome this plasticity but requires coordinated delivery of two inhibitors to the same cell. Here we design a glycyrrhizic acid (GA) nanogel that functions as both a structural carrier and a prodrug. GA itself serves as the structural carrier. It hydrolyzes in the acidic tumor microenvironment to become glycyrrhetinic acid (GRA), an OXPHOS inhibitor. The nanogel also encapsulates mannose, a glycolysis inhibitor. A crisis-inducing nanogel (CNG) is fabricated via Fe2+-crosslinked borate networks using microfluidic assembly, enabling pH-responsive disassembly. Fe2+ serves as both a structural crosslinker and a therapeutic component for ferroptosis. Upon exposure to acidic pH, CNG synchronously releases mannose and converts GA to GRA. Mannose suppresses glycolysis, GRA inhibits OXPHOS, and together they induce severe ATP depletion and bioenergetic collapse, which directly activates transient receptor potential cation channel subfamily M member 4 (TRPM4) ion channels. This activation triggers pathological Na+ influx and a cell death modality referred to as necrosis induced by sodium overload (NECSO). Simultaneously, liberated Fe2+ catalyzes the Fenton reaction, driven lipid peroxidation, and triggers ferroptosis. The convergence of NECSO and ferroptosis amplifies immunogenic cell death. In a 4T1 breast cancer model, CNG suppresses tumor growth and remodels the immunosuppressive microenvironment without systemic toxicity. This work establishes a "carrier-as-prodrug" nanoplatform that co-delivers two metabolic inhibitors with spatiotemporal precision. It also identifies TRPM4 as a mechanistically linked ion channel target in energy-stressed tumors.