Abstract

Age-related nicotinamide adenine dinucleotide (NAD + ) deficiency is implicated in numerous pathologies, including dry age-related macular degeneration (AMD). Current NAD + -boosting strategies, reliant on precursors like nicotinamide mononucleotide (NMN), necessitate repeated dosing and offer transient effects, limiting therapeutic utility. Here, we address this critical limitation by developing a single-dose therapy using circular mRNA (circ-mRNA) to deliver functional nicotinamide phosphoribosyl transferase (NAMPT), the essential rate-limiting enzyme in NAD + salvage. Engineered via permuted intron-exon (PIE) splicing, our circNAMPT exploits the exceptional stability and persistent translation capacity inherent to circular RNA scaffolds. Encapsulation in β-sitosterol-optimized lipid nanoparticles (LNPs) ensures robust intracellular delivery. In vitro, circNAMPT-LNP drives sustained NAMPT expression and prolonged NAD + elevation, circumventing precursor limitations. In a stringent sodium iodate-induced dry AMD model, a single intravitreal circNAMPT-LNP injection matched the neuroprotective efficacy of 14 consecutive daily intraperitoneal NMN doses confirmed by histological integrity and functional preservation. This work establishes engineered circ-mRNAs as a transformative platform for durable, single-dose therapeutic protein delivery and demonstrates potential as a disease-modifying therapy for dry AMD. Its applicability extends broadly to systemic disorders driven by NAD + deficiency in aging.