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

Feifei Chen,1,* Hui Jiang,2,* Xueyi Song,3 Jianfeng Wang,3 Xu Ma,4 Quan Zhou,3 Abdullah Al Mamun,5 Lingna Li,6 Yunfang Zhou,3 Hongbin Xu,1 Shuanghu Wang3 1Department of Pharmacy, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, People’s Republic of China; 2Department of Pharmacy, The People’s Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, 530021, People’s Republic of China; 3Central Laboratory of Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People’s Hospital, Lishui, 323000, People’s Republic of China; 4Department of Pediatric Orthopaedics, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, People’s Republic of China; 5Department of Pharmacy, American International University-Bangladesh (AIUB), Dhaka, 1229, Bangladesh; 6Department of Pharmacy, The Affiliated Hospital of Ningbo University, LiHuiLi Hospital, Ningbo, 315010, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongbin Xu; Shuanghu Wang, Email [email protected]; [email protected]: 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.Keywords: ischemic stroke, hollow mesoporous silica nanoparticles, imperatorin, Nrf2/ARE/Keap1 pathway