Alendronate carbon dots targeting bone immune microenvironment for the treatment of osteoporosis

Abstract

Bisphosphonates (BPs) are some of the most widely used drugs in osteoporosis (OP) treatment, but they can cause severe side effects such as bisphosphonate-related osteonecrosis of the jaw (BRONJ), causing great pain in patients. It is necessary to develop a novel drug for treating OP with fewer side effects. In this study, novel carbon dots, ALEN-CDs, derived from polyethylene glycol (PEG) and alendronate (ALEN) are developed. ALEN-CDs have good biocompatibility, photoluminescence (PL) properties, and bone-targeting ability. They can inhibit the differentiation and maturation of osteoclasts, play an immunoregulatory role by inhibiting macrophage polarization to the pro-inflammatory M1 phenotype, and promote polarization to the anti-inflammatory M2 phenotype. It is worth noting that compared with ALEN, high-dose applications of ALEN-CDs do not lead to BRONJ, which may be related to the regulatory effect on M2 macrophage polarization. Moreover, in vivo studies show that ALEN-CDs significantly reduce bone loss and improve OP in ovariectomized mice (OVX). And a proteomic analysis suggestes that ALEN-CDs regulate the bone immune microenvironment by affecting mitochondrial metabolism, especially oxidative phosphorylation (OXPHOS). In conclusion, ALEN-CDs could directly inhibit osteoclast differentiation and regulate the bone immune microenvironment and may be a promising drug for OP treatment.