Targeted restoration of mitochondrial function mediates autophagy and glycolysis to promote irradiation-induced bone injury repair

Radiotherapy remains a critical modality for tumor eradication in clinical practice. However, the bone tissue surrounding the tumor is highly susceptible to irradiation-induced damage due to its high density. Irradiation disrupts the dynamic balance between osteogenesis and osteoclastogenesis by inducing mitochondrial dysfunction and oxidative stress, and effective treatments for irradiation-induced bone loss are currently lacking. In this study, we evaluated 25 patients who received radiotherapy and observed a decrease in rib bone mass following treatment. This finding was further validated in a rat model, where X-ray irradiation led to bone loss associated with mitochondrial dysfunction. Here, we developed a (5-carboxypentyl) triphenylphosphonium bromide (TPP-COOH)-functionalized hollow manganese dioxide nanoparticle (hMNP-TPP). After loading with mitochondrial PCK2, the resulting PCK2@hMNP-TPP was immobilized on an oxidized hyaluronic acid/gelatin (HG) anisotropic scaffold (PCK2@hMNP/HG) to serve as a multifunctional platform for mitochondrial-targeted reactive oxygen species (ROS) scavenging and metabolic reprogramming. PCK2@hMNP-TPP was released from the scaffold in response to an acidic microenvironment. The surface-bound TPP enabled mitochondrial targeting via charge interactions, allowing the nanoparticles to scavenge mitochondrial ROS, restore membrane potential and ATP synthesis, and inhibit osteoclastogenesis. Following ROS elimination, PCK2 released from the nanoparticles promoted bone regeneration through dual activation of ERK-mediated glycolysis and autophagic flux, synergistically enhancing osteogenesis while suppressing osteoclast differentiation. In a murine radiation model of irradiation-induced bone injury (20 Gy), PCK2@hMNP-TPP restored trabecular architecture without causing systemic toxicity. Collectively, the hMNP-immobilized anisotropic scaffold represents a promising platform for restoring bone metabolism through targeted modulation of mitochondrial function, offering a precise strategy for the treatment of irradiation-induced bone injury. Mitochondria plays a key role in cellular function and bone metabolism. However, bone mass was decreased after receiving radiotherapy due to the disruption of mitochondrial function. To promote the repair of irradiation-induced bone injury, the multifunctional hollow manganese dioxide nanoparticle (hMNP)-immobilized anisotropic scaffold (PCK2@hMNP/HG) was developed. In the acidic microenvironment of bone injury, the released hMNP-TPP targeted accumulated to mitochondria due to charge interaction, efficiently improving mitochondrial function and inhibiting osteoclast formation. After scavenging reactive oxygen species (ROS), the released PCK2 presented obvious osteoinductive activity by dual activation of ERK-mediated glycolysis and autophagy, enhancing regeneration of radiation-induced bone injury. In summary, the developed hMNP-based platform may be a promising candidate for precisely regulating mitochondrial function to accelerate the repair of irradiation-induced bone injury.