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

초록

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.

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