Nanoparticles with reprogramming of mitochondrial respiratory chain complex and epigenetic modifications functions for osteoporosis treatment.

Abstract

Current therapies primarily focusing on osteoporosis often fail to address the root relationship between metabolic reprogramming and epigenetic modification alterations. Developing an efficient therapeutic approach with dual-pronged functionality for the treatment of osteoporosis represents a noteworthy challenge. Herein, samples from humans and rats with osteoporosis presented in this study underscore the correlation between mitochondrial metabolism, epigenetic modifications, and osteoporotic bone loss. Inspired by this, we focus on designing a nano-therapy that serves as a strategy, targeting both the maintenance of metabolic homeostasis and the modulation of epigenetic modifications, thereby achieving a dual-functional effect in the treatment of osteoporosis. Accordingly, 4-octyl itaconate (OI), which exhibits immunometabolic activity and regulates epigenetic modifications, was encapsulated within mesoporous silica (MSN) and further modified with a cerium ion-coordinated tannic acid (Ce-TA) supramolecular network on its surface for boosting antioxidant properties. In brief, MSN-OI@Ce-TA (MOCT NPs) exhibit synergistically enhanced antioxidant capabilities in pro-inflammatory macrophages and alleviates osteoporotic bone loss by restoring mitochondrial respiratory chain complex function, remodeling DNA and histone modifications, and thereby restoring osteoimmune homeostasis. Overall, these findings highlight the compelling dual treatment mechanisms of MOCT NPs, providing a theoretical basis for the management of osteoporosis.