Dual-Targeting Nanoparticles Enhance Microglial P2Y12R Expression to Promote Neuronal Mitophagy for Repairing Spinal Cord Injury

Spinal cord injury (SCI) leads to severe mitochondrial dysfunction and ROS cascade, with microglia playing a dual role in both exacerbating damage and providing neuroprotection. Recent evidence has highlighted the importance of P2Y12R in microglial-neuron interactions, particularly in modulating mitochondrial quality control and mitigating oxidative stress. Here, we develop a dual-targeting nanoparticle system (P2Y-Nano) to enhance P2Y12R expression in activated microglia and promote neuronal mitophagy, aiming to reduce mitochondrial reactive oxygen species (mtROS) and improve neuronal survival following SCI. The P2Y-Nano system combines a ROS-responsive thioketal bond for injury-site targeting with an MG1 peptide to selective target activated M1 microglia. This design enables precise nanoparticle delivery to the ROS-enriched injury microenvironment, effectively restoring P2Y12R expression in microglia. Microglia treated with P2Y-Nano exhibit elevated P2Y12R expression, leading to increased interaction with injured neurons, improved mitophagy, and reduced mtROS production. These combined effects significantly attenuate secondary damage and contribute to neuroprotection post-SCI. Our findings reveal a novel regulatory mechanism by which P2Y12R overexpression in microglia enhances neuronal mitophagy and mitigates oxidative stress after SCI. The dual-targeting P2Y-Nano system offers a promising therapeutic approach not only for SCI but also for other CNS disorders characterized by microglial activation and mitochondrial dysfunction.