Mus musculus Transcriptome or Gene expression
Radiotherapy remains a critical modality for tumor eradication in clinical practice. Bone tissue surrounding the tumor is highly susceptible to irradiation damage due to its high density. The dynamic balance of osteogenesis and osteoclastogenesis is disrupted by irradiation-induced mitochondrial dysfunction and oxidative stress. However, there are currently no effective treatments for radiation-induced bone loss. In this study, we screened 25 patients who received radiotherapy and found that the bone mass of ribs was decreased after radiotherapy. Then the measurement in rats was further confirmed that X-ray irradiation caused bone loss due to mitochondrial dysfunction. Here, we developed a (5-carboxypentyl) triphenylphosphonium bromide (TPP-COOH) functionalized hollow manganese dioxide nanoparticle (hMNP-TPP). After loading mitochondrial PCK2, the obtained PCK2@hMNP-TPP was immobilized on oxidized hyaluronic acid/gelatin (HG) anisotropic scaffold (PCK2@hMNP/HG) as a multifunctional platform for mitochondrial-targeted reactive oxygen species (ROS) scavenging and metabolic reprogramming. PCK2@hMNP-TPP responded to acidic microenvironment and was released from PCK2@hMNP/HG. Then TPP on the surface of PCK2@hMNP-TPP directed nanoparticles to mitochondria due to charge interaction, scavenging mitochondrial ROS, rescuing membrane potential and ATP synthesis and inhibiting osteoclastogenesis. Subsequently, PCK2 released from PCK2@hMNP-TPP after eliminating ROS orchestrated bone regeneration by dual activation of ERK-mediated glycolysis and autophagy flux, synergistically enhancing osteogenesis while suppressing osteoclast differentiation. In a murine radiation model (20 Gy), PCK2@hMNP-TPP restored trabecular architecture without systemic toxicity. Taken together, the hMNP-immobilized anisotropic platform is a promising tool to restore bone metabolism via targeted regulation of mitochondrial function for precisely repairing irradiation-induced bone injury.