Imaging Study of MnO2-Based Nanomotors Modulating HIF-1α/Lipid Droplet Biogenesis and Activating the cGAS-STING Pathway

The overexpression of hypoxia-inducible factor-1α (HIF-1α) suppresses STING signaling and modulates lipid metabolism in tumor cells, leading to abnormal lipid droplet (LD) accumulation. Herein, we constructed a manganese dioxide (MnO₂)-based nanomotor (HMIP@A). HMIP@A depletes intracellular hydrogen peroxide (H₂O₂) and glutathione (GSH) to generate oxygen (O₂), Reactive Oxygen Species (ROS), and manganese (Mn²⁺). A dual strategy of "oxygen supplementation" and "small-molecule inhibition" synergistically downregulates HIF-1α, thereby suppressing LD biogenesis. This process sensitizes tumor cells to ROS, leading to severe DNA damage. Released Mn²⁺ and damaged DNA synergistically activate the Cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) pathway. In vitro, HMIP@A markedly increases ROS production, lipid peroxidation (LPO), and DNA damage, thereby inducing tumor cell death, immunogenic cell death (ICD), and dendritic cell (DC) maturation. Furthermore, HMIP@A exhibits excellent penetration in tumor spheroids. Overall, this study provides a theoretical basis for the design of nanomedicines through a strategy integrating metabolic intervention, oxidative damage sensitization, and immune activation.