Neutrophil-Membrane Biomimetic Hollow Mesoporous Silica Nanoparticles for Targeted Delivery of Imperatorin to Alleviate Cerebral Ischemia–Reperfusion Injury via Nrf2/ARE/Keap1 Pathway

Introduction: Cerebral ischemic stroke has high mortality and disability rates with limited targeted therapeutic strategies. Biomimetic nanocarriers can optimize drug delivery efficiency and exert neuroprotection effects, providing a promising strategy for ischemia-reperfusion injury treatment. Methods: Hollow mesoporous silica nanoparticles (HMSNs) were synthesized via an improved Stoer method and loaded with imperatorin (IMP). Subsequently, neutrophil cell membranes (NCM) extracted from DMSO-induced HL-60 cells were coated onto the nanoparticles to construct NCM/IMP@HMSNs. Nanomaterial characterization was carried out. In vitro oxygen-glucose deprivation/reoxygenation (OGD/R) models in SH-SY5Y cells and in vivo rat middle cerebral artery occlusion/reperfusion (MCAO/R) models were established to explore the underlying neuroprotective mechanisms. Results: The synthesized NCM/IMP@HMSNs nanoparticles possessed uniform particle size (~143 nm) and favorable stability, with an encapsulation efficiency of 31.84%. In vitro results revealed that IMP significantly increased the viability of OGD/R-injured SH-SY5Y cells compared with the model group. In vivo experiments showed that NCM/IMP@HMSNs efficiently accumulated in ischemic brain tissue, notably decreased mNSS scores, and reduced cerebral infarct volume by approximately 33.31% compared with the MCAO/R group. This nanosystem activated the Nrf2/ARE/Keap1 pathway, thereby upregulating HO-1 expression to strengthen antioxidant capacity, alleviate the accumulation of cerebral oxidative stress products, and regulate the activities of SOD, GSH, CAT and LDH. Conclusion: The biomimetic NCM/IMP@HMSNs nanoplatform enhances the neuroprotective efficacy against ischemia–reperfusion injury via activating the Nrf2/ARE/Keap1 pathway, offering a promising targeted therapeutic approach for ischemic stroke therapy.