2. Academic Validation
  3. Single intravitreal injection of lipid nanoparticles delivering circular mRNA of nicotinamide phosphoribosyltransferase protects against dry AMD

Single intravitreal injection of lipid nanoparticles delivering circular mRNA of nicotinamide phosphoribosyltransferase protects against dry AMD

  • J Control Release. 2026 Apr 10:392:114691. doi: 10.1016/j.jconrel.2026.114691.
Hui-Lin Li 1,  Yu Xu 1,  Jian-Shan Mo 2,  Xin-Yuan Zhao 1,  Cai-Ling Zhong 3,  Zi-Wen Jia 1,  Xiao-Long Wang 1,  Ben-Chi Zhao 1,  Yan-Ming Chen 4,  Ke-Wei Zheng 5,  Xiao-Lei Zhang 6,  Qiao-Ping Wang 7
Affiliations

Affiliations

  • 1 Laboratory of Metabolism and Aging, School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China.
  • 2 National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 3 School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China.
  • 4 Department of Endocrinology and Metabolic Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China; Department of Endocrinology and Metabolic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518033, China; Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, China.
  • 5 School of Biomedical Sciences, Hunan University, Changsha 410082, China. Electronic address: [email protected].
  • 6 National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: [email protected].
  • 7 Laboratory of Metabolism and Aging, School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, China; State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: [email protected].
PMID: 41672305 DOI: 10.1016/j.jconrel.2026.114691
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.

Keywords

Age-related macular degeneration; Aging; Circular mRNA; Drug delivery; Nicotinamide adenine dinucleotide; Nicotinamide phosphoribosyltransferase.

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