ZIF-8-gated cascade nanoreactor amplifies glucose-triggered CO release and ferroptosis for mild photothermal cancer therapy.

Mild photothermal therapy offers a safer alternative to conventional hyperthermia, but its therapeutic efficacy is frequently compromised by heat-shock protection, metabolic compensation and insufficient intracellular oxidative damage. Herein, we developed a ZIF-8-gated cascade nanoreactor, denoted ZIF/HMPB-CO@GOx, to amplify glucose-triggered carbon monoxide release and ferroptosis for enhanced mild photothermal cancer therapy. In this system, hollow mesoporous photothermal nanocores were loaded with a CO donor and glucose oxidase, followed by ZIF-8 coating as an acid-responsive gatekeeper. The ZIF-8 shell protected the catalytic payloads under physiological conditions and promoted intracellular release in acidic environments. Upon 808 nm laser irradiation, the nanoreactor generated nonablative mild hyperthermia and accelerated cascade reactions in which GOx catalyzed glucose oxidation to produce H2O2, thereby coupling glucose metabolism to CO liberation and redox amplification. The combined metabolic actions suppressed glycolysis and mitochondrial oxidative phosphorylation, resulting in ATP depletion and lactate reduction; these changes were accompanied by reduced HSP70 protein abundance. Meanwhile, GSH depletion, reduced GPX4 protein abundance and lipid-peroxidation-associated readouts supported ferroptotic involvement, together with partial rescue by ferrostatin-1. In 4T1 tumor-bearing mice, ZIF/HMPB-CO@GOx enabled tumor accumulation, controlled mild photothermal heating and pronounced tumor growth suppression without obvious body-weight loss. This ZIF-8-gated nanoreactor establishes a glucose-powered gas-releasing strategy to reduce reliance on high-temperature thermal ablation while coupling metabolic disruption with ferroptosis-related oxidative damage.