Abstract

Neuroinflammation mediated by microglia and excessive oxidative stress are key pathological processes driving the progression of brain injuries such as intracerebral hemorrhage (ICH) and traumatic brain injury (TBI). Modulating lactate transport has emerged as a promising approach to mitigate M1 microglia polarization and alleviate neuroinflammation. Liposomal nanoparticles provide a safe and efficient platform for drug delivery. Here, we developed reactive oxygen species (ROS) responsive MiRCM nanoparticles that co-deliver monocarboxylate transporter 1 (MCT1) inhibitor AR-C155858 and a ROS-scavenging PPS core, modified with CAQK and MG1 peptides for brain injury site and microglia targeting. MiRCM nanoparticles demonstrated ROS-induced degradation and controlled drug release, effectively protecting AR-C155858 from enzymatic degradation. In vitro and in vivo experiments exhibited that MiRCM nanoparticles selectively accumulated at injured brain regions and in M1-type microglia, where they scavenged ROS, inhibited lactate efflux, suppressed M1 microglia polarization and reduced inflammatory cytokine production in ICH and TBI models. Consequently, MiRCM treatment protected neurons, reduced astrocyte activation, preserved blood-brain barrier integrity, enhanced endogenous antioxidant enzyme activities, and alleviated neurological deficits in both ICH and TBI models. RNA sequencing further confirmed downregulation of inflammatory pathways. Moreover, biosafety evaluations revealed no significant histopathological or biochemical abnormalities in major organs, indicating good biocompatibility. In summary, this study offers a new MiRCM nanoparticle that effectively modulates lactate transport and eliminates ROS to suppress microglia M1 polarization and neuroinflammation, ultimately enhancing neural protection and functional recovery after ICH and TBI.