Polydopamine-modified mesoporous silica nanoparticles loaded with AM1241 alleviate cerebral ischemia-reperfusion injury

Cerebral ischemia-reperfusion injury arises predominantly from excessive oxidative stress and sustained neuroinflammation. The selective cannabinoid receptor type 2 (CB2R) agonist AM1241 has shown potential to alleviate both pathological processes, yet its therapeutic efficacy is severely hampered by poor blood-brain barrier (BBB) permeability and inadequate intracerebral accumulation. To elevate the intracerebral therapeutic efficacy of AM1241, we constructed polydopamine-modified mesoporous silica nanoparticles (PMSNs) as nanocarriers to encapsulate AM1241, generating PMSNs@AM1241. Comprehensive physicochemical characterization confirmed that these nanoparticles exhibited uniform morphology, excellent dispersion, reliable storage stability, and pH-responsive drug release, enabling rapid AM1241 release in acidic environments. In vitro studies demonstrated that PMSNs@AM1241 exhibited high biocompatibility, could efficiently penetrate the blood-brain barrier, and were readily internalized by microglia. The nanomedicine effectively scavenged reactive oxygen species and suppressed neuronal apoptosis. It also inhibited the release of pro-inflammatory cytokines and reduced M1-like microglial marker expression while increasing M2-like marker expression via activation of CB2R and inhibition of the NF-κB signaling pathway, thereby exerting neuroprotective effects. In vivo, PMSNs@AM1241 significantly reduced brain edema, decreased infarct volume, attenuated histopathological damage, inhibited neuronal apoptosis, and markedly ameliorated neurological deficits in mice. Notably, the intrinsic antioxidant activity of PMSNs combined with the anti-inflammatory activity of AM1241 cooperatively modulated microglial inflammatory responses via the NF-κB signaling pathway, thereby attenuating oxidative stress and inflammatory cascades. Collectively, PMSNs@AM1241 represents an effective nanodelivery platform for cerebral ischemia-reperfusion injury, providing a novel strategy and experimental foundation.