Mitochondria-loading erythrocytes transfer mitochondria to ameliorate inflammatory bone loss

Abstract

Inflammatory diseases frequently result in bone loss, a condition for which effective therapeutic interventions are lacking. Mitochondrial transfer and transplantation hold promise in tissue repair and disease treatments. However, the application of mitochondrial transfer in alleviating disorders has been limited due to its uncontrollable nature. Moreover, the key challenge in this field is maintaining the quality of isolated mitochondria (Mito), as dysfunctional Mito can exacerbate disease progression. Therefore, we employ Mito-loading erythrocytes (named MiLE) to achieve maintenance of mitochondrial quality. In addition, MiLE can be cryopreserved, allowing for long-term preservation of mitochondrial quality and facilitating the future application of mitochondrial transfer. In the inflammatory microenvironment, MiLE supplies Mito as well as O₂ to macrophages. By undergoing metabolic reprogramming, MiLE suppresses lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction. In summary, this work tackles the challenges of uncontrollable mitochondrial transfer and mitochondrial quality maintenance, and offers an opportunity for future exploration of organelle transplantation.

Statement of significance

The application of mitochondrial transfer for the alleviation of pathologies has been hindered by the intrinsic limitations in terms of control and selectivity. Furthermore, maintaining mitochondrial integrity and functionality following isolation poses a significant challenge. In a pioneering approach, we develop a method for encapsulating mitochondria within erythrocytes, termed mitochondria-loading erythrocytes (MiLE), which ensures extended mitochondrial functionality and controlled transfer. Within an inflammatory microenvironment, MiLE supplies both mitochondria and O₂ to macrophages. By undergoing metabolic reprogramming, MiLE alleviates lipopolysaccharide-induced osteoclast differentiation and promotes macrophage polarization from M1 to M2 phenotype, ultimately ameliorating inflammatory bone destruction.