Intraoperative application of an antioxidant nanoparticle-hydrogel targeting microglia regulates neuroinflammation in traumatic brain injury

Microglia play a critical role in neuroinflammation, a key secondary injury mechanism following traumatic brain injury (TBI). The colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 has shown promise in suppressing neuroinflammation by depleting microglia, but it lacks specificity in targeting microglia at the injury site. To overcome this limitation, we developed PLX5622 nanoparticles functionalized with the CAQK peptide for lesion-specific targeting and combined them with a hydrogel (GelMA-PPS) that possesses potent reactive oxygen species (ROS) scavenging capabilities. This nanoparticle-hydrogel drug delivery system (GelMA-PPS/P) significantly enhanced the delivery efficiency and therapeutic efficacy of PLX5622 in TBI treatment. Localized administration of this system effectively depleted microglia at the injury site, suppressed neuroinflammation, and reduced the release of inflammatory cytokines. Its ROS scavenging ability was also validated in vitro and in vivo. Together, these effects synergistically improved neurological function recovery in TBI mouse models. This innovative strategy offers a comprehensive and targeted approach to managing neuroinflammation after TBI, providing a promising avenue for advancing TBI therapies.