Synergistic antioxidant and gene supplementation for high-efficacy retinitis pigmentosa therapy

(rd10) retinas revealed early and progressive dysregulation of oxidative stress-related pathways and photoreceptor degeneration. To overcome this barrier, we engineered an adeno-associated virus (AAV) vector covalently conjugated with a catalytic G-quadruplex-hemin DNAzyme (CoG4) via genetic code expansion and click chemistry. This design enables synchronized delivery of CoG4 and therapeutic Pde6b into photoreceptors, where CoG4 directly scavenges excess ROS and restores mitochondrial homeostasis, thereby creating a favorable microenvironment for gene supplementation. In rd10 mice, AAV-CoG4 treatment resulted in sustained expression of Pde6b, preservation of photoreceptor morphology, restoration of rod and cone function as evidenced by electroretinogram, and improved visual behavior, outperforming AAV or CoG4 monotherapies. Our findings establish oxidative stress as a major barrier to retinal gene therapy and demonstrate a dual-function platform that couples microenvironment modulation with genetic correction, offering a broadly applicable strategy for treating degenerative retinal diseases.