Endogenous/exogenous dual stimulation “ROS engineering” amplification combined with autophagy-augmented for efficient ferroptosis therapy

“Reactive oxygen species (ROS) engineering” is one of the most promising anti-tumor treatments developed in recent years. Massive explosion of ROS will cause oxidative stress, thereby inducing tumor cell death. However, ROS accumulation in tumor cells is eliminated by endogenous cellular self-regulation strategies. In this work, a kind of endogenous/exogenous dual stimulation nanoagent noted as UMZC is developed. Fenton reaction occurs between NH₂-MIL-88B(Fe) contained in UMZC and the overexpression of endogenous H₂O₂ to generate ROS, amplified by endogenous H₂S of colon tumor cells. In addition, NH₂-MIL-88B(Fe) also functions to deplete glutathione (GSH) for stopping it from consuming ROS. Upconversion nanoparticles at the core of UMZC convert near-infrared into visible light, which excites zinc phthalocyanine to initiate the photochemical reaction that generates more ROS, thus alleviating the lack of tissue penetration depth for visible light. Autophagy agonist chitosan oligosaccharides induce enhancement of cellular autophagy for disrupting cellular metabolic stress and the resistance to oxidative stress of tumor cells, allowing “ROS engineering” to fully exert anti-tumor effects. All of ROS generation, GSH depletion, and induced cellular autophagy caused by nanoagents have promoting effects on the occurrence of ferroptosis. Finally, the nanoagents show the ability to effectively treat colon tumors.