Localized Nicotinamide Riboside Delivery Through a Reversible Affinity Hydrogel Promotes Myocardial Restoration

ABSTRACT

Myocardial infarction (MI), a major cause of cardiovascular morbidity and mortality, is characterized by acute ischemic injury followed by mitochondrial dysfunction, inflammation, redox imbalance, and adverse cardiac remodeling. NAD ⁺ ‐a vital coenzyme—is rapidly perturbed after MI and represents a potential metabolic target for supporting myocardial recovery. However, existing biomaterial formulations have limited efficacy because of their insufficient loading and local delivery of NAD ⁺ and other small hydrophilic molecules to the myocardium. Herein, we present an injectable, on‐heart adhesive hydrogel capable of efficiently loading and gradually releasing nicotinamide riboside (NR), a precursor of NAD ⁺ , to restore NAD ⁺ levels in infarcted cardiac tissue. Phenylboronate‐modified chitosan forms reversible yet high‐affinity interactions with NR, enabling controlled delivery; while the hydrogel network is engineered from crosslinking with gallol‐modified chitosan that provides tissue adhesion and facilitates in situ gelation upon injection. In a murine MI model, hydrogel‐mediated NR delivery increased NAD ⁺ availability and improved cardiac function and electrophysiology. Benefits included reduced injury, improved redox and metabolic function, and preserved cardiac structure. Mechanistically, NR protection converged on the SIRT1–p65 axis, limiting ferroptotic and inflammatory injury while preserving mitochondrial function. Thus, the hydrogel provides a cardiac‐adhesive platform for NR delivery, restoring NAD ⁺ homeostasis and promoting recovery after MI.