A sustained-release depot formulation of β-nicotinamide mononucleotide for alleviating chemotherapy-induced myelosuppression

Chemotherapy-induced myelosuppression (CIM) is characterized by impaired hematopoietic function and a sharp decline in peripheral blood cell counts. To address this issue, we developed a sustained-release depot microsphere formulation to deliver β-nicotinamide mononucleotide (NMN-MS) with improved systemic bioavailability. The experiments in vitro and in vivo demonstrated that NMN-MS could effectively alleviate chemotherapy-induced reduction of peripheral blood cells and bone marrow nucleated cells (BMNC), suppress BMNC apoptosis, promote the secretion of hematopoietic cytokines, and significantly enhance hematopoietic stem cell counts, thereby facilitating the recovery of bone marrow function. The results of histopathological examination further confirmed that NMN-MS treatment could markedly attenuate chemotherapy-induced femoral and splenic tissue injury in model mice. Mechanistically, NMN-MS upregulated the phosphorylation of PI3K and Akt, while increasing the expression of p-PTEN and Bcl-2 proteins. Inhibitor assays further confirmed that inhibition of PI3K or AKT abolished these protective effects, indicating that the PI3K-PTEN-AKT-Bcl-2 signaling axis plays a critical, albeit non-exclusive, mediator of NMN-MS-induced HSC proliferation and hematopoietic recovery. Collectively, our findings highlight NMN-MS as a promising therapeutic strategy for the prevention and intervention of CIM.