Harmonizing NAD ⁺ metabolism with CeMOF nanozyme to orchestrate intraocular pressure modulation for glaucoma treatment

Abstract Elevated intraocular pressure (IOP) is a critical risk factor for the development and progression of glaucoma. However, current treatments focus primarily on mechanical stress relief, neglecting the underlying issue of diminished cellular energy production in patients. In this study, we investigated the impact of NAD + reduction on IOP regulation and explored the potential of NAD + precursors as a therapeutic strategy. We investigated the role of NAD + metabolism in glaucoma and revealed decreased nicotinamide phosphoribosyltransferase (NAMPT) expression in both patients and the human trabecular meshwork (HTM) cell model. Supplementation with NAD + precursors, nicotinamide (NAM) or nicotinamide mononucleotide (NMN), provided protective effects in H 2 O 2 ‐treated HTM cells and reduced IOP in ocular hypertension mouse models by mitigating senescence, extracellular matrix accumulation, and oxidative stress. To optimize drug delivery, we engineered the NAM@CeMOF‐2 nanozyme system, which achieved a maximum IOP reduction in Cav1 ⁻/⁻ mice following 7 days of treatment. This localized treatment improved bioavailability and reduced systemic side effects. These findings suggest that NAD + deficiency plays a role in glaucoma development and propose novel therapeutic targets for addressing cellular dysfunction in glaucoma.