Acute kidney injury (AKI) is characterized by renal tubular epithelial cell damage, an inflammatory cascade, and oxidative stress, leading to acute renal failure. Nicotinamide mononucleotide (NMN), a potential nephroprotective agent, activates the SIRT1 pathway by supplementing NAD + , promoting cell repair and antioxidation. However, its clinical application is limited by poor bioavailability, rapid metabolic clearance, and other pharmacokinetic constraints, necessitating frequent dosing to maintain therapeutic efficacy. To address these challenges, we developed a pH-responsive, biodegradable nanoparticle system, CS-NMN, based on chitosan (CS). The system was prepared via ion gelation, combining the biocompatibility and cationic tubular targeting properties of CS with the NAD + supplementation effect of NMN. At physiological pH, the ionization of amines on CS weakens electrostatic crosslinking, promoting prolonged NMN release. In the acidic microenvironment typical of AKI, the nanoparticle structure becomes denser, slowing the release and ensuring stable encapsulation during the acute injury phase, with targeted delivery during the recovery phase. The CS-NMN nanoparticles exhibit uniform particle size and excellent dispersity, with FTIR analysis confirming successful ionic crosslinking and encapsulation efficiency of up to 86.53%. In vitro release studies demonstrated a cumulative release rate of 70% at pH 7.4, significantly higher than at pH 6.6 and pH 5.6. The developed CS-NMN nanoparticle system ameliorates tubular injury via activating the SIRT1 signaling pathway. This activation subsequently suppresses the key pro-inflammatory NF-κB pathway, mitigating oxidative stress and cellular apoptosis. Ultimately, this targeted intervention rescues mitochondrial integrity and function, breaking the vicious cycle of damage and promoting tubular repair in AKI. This system provides a multifunctional nanoparticle platform integrating pH-responsive delivery and biodegradability for targeted AKI therapy, demonstrating excellent biocompatibility and clinical translational potential.
