A multifunctional and ROS response CO-gas delivery platform for spinal cord regeneration.

Spinal cord injury (SCI) initiates a cascade of pathological events in which neuroinflammation and hypoxia critically impair functional recovery. Although exogenous carbon monoxide (CO) exhibits anti-inflammatory potential, its translation has been hindered by the lack of a safe and effective delivery strategy. Here, we report the development of a multifunctional therapeutic platform (COPH), composed of CO-releasing molecules-401 (CORM-401) as the CO donor, peptide dendrimer nanogels (PDNs) as the carrier, and hyaluronic acid (HA) as a microglia-targeting ligand. COPH selectively accumulates in microglia, where it responds to elevated reactive oxygen species (ROS) by releasing CO and simultaneously scavenging excessive ROS. In vitro and in vivo studies demonstrate that COPH suppresses pro-inflammatory mediators such as IL-1β and CD86 via inhibition of the NF-κB/p65 pathway, while promoting M1-to-M2 microglial polarization. Moreover, CO released from COPH alleviates local hypoxia by modulating hemoglobin-oxygen binding dynamics, thereby enhancing oxygen availability to neurons and vascular cells in ischemic regions. Through activation of the Nrf2/HO-1 antioxidant pathway, COPH further mitigates oxidative stress and reduces neuronal apoptosis. Collectively, these findings highlight COPH as a targeted CO delivery system that attenuates inflammation, relieves hypoxia, and protects neurons after SCI, providing a promising strategy for CO-based therapeutics in neurotrauma.