Drug loaded cerium oxide nanozymes prevent radiation-Induced cataracts via suppressing the cGAS-STING pathway

Abstract Radiation-induced cataracts (RIC), a significant cause of blindness, arise from oxidative damage and inflammation in the lens epithelium, and there has been a lack of effective targeted therapeutic drugs in clinic. Here, we proposed and developed a novel approach for prevention and treatment of RIC via multifunctional nanozymes. We first demonstrated activation of the cGAS-STING pathway can drive mitochondrial oxidative stress and cytosolic double-stranded DNA (dsDNA) accumulation in ionizing radiation (IR)-exposed lens epithelial cells (LECs). Accordingly, a nanozyme-based drug delivery system, namely porous CeO 2 loaded with STING inhibitors H-151 (CeO 2 @H-151), was developed for RIC prevention and treatment. Importantly, CeO 2 @H-151 nanozymes not only decreased reactive oxygen species (ROS) production induced by mitochondrial oxidative injury, but also reduced inflammation caused by increased dsDNA. This can be attributed to the synergistic effect of antioxidant, anti-inflammation and protein homeostasis-preserving of CeO 2 @H-151 nanozymes. It also revealed CeO 2 @H-151 nanozymes exerted protein homeostasis preservation through H-151 bound to the Cys172 oxidative modification site of PRDX2. This work provides a synergistic nanotherapeutic strategy targeting the cGAS-STING pathway, offering a promising approach for preventing and treating RIC and even other oxidative-inflammatory disorders. Graphical Abstract