Functionalized biomimetic nanoparticles are delivered from the nose to the brain for the synergistic targeted treatment of cerebral ischemia/reperfusion injury.

The pathology of cerebral ischemia/reperfusion (CIR) injury is complex. Additionally, single drugs have shown limited efficacy, and their delivery has encountered obstacles, such as the blood-brain barrier and poor targeting effects. Therefore, we designed a biomimetic nanoparticle: PR-M2/BED@BA was composed of boric acid ester-grafted dextran (BED) loaded with the drug baicalin (BA) and modified with an M2 microglial membrane and protamine sulfate (PR). Moreover, PR-M2/BED@BA homed to the brain lesion after entering the transnasal mucosa and released BA in response to the high content of reactive oxygen species in the microenvironment. In vitro studies have shown that BED has the ability to scavenge reactive oxygen species. PR-M2/BED@BA can rapidly release BA in an H₂O₂ environment, significantly enhancing the transport capacity across the nasal mucosal barrier and the uptake by microglia and neurons. In vivo studies showed that PR-M2/BED@BA significantly increased the amount of drug released into the brain, improved the neurobehavioral score and ameliorated pathological damage to the brain tissue in mice with global cerebral ischemia. This neuroprotective effect was related to the regulation of microglial polarization to reduce the inflammatory response, reduce microglial oxidative stress, and thus, reduce neuronal apoptosis. Overall, this study provides a new strategy for nasal-brain drug delivery and new ideas for the treatment of CIR injury and other neurological diseases.