Etanercept-Loaded Nanoniosomes for Microglial M2 Polarization and Neuroinflammation Reduction in Ischemic Stroke Rats Publisher



Kouhbanani MAJ ; Adeli S ; Hassanzadeh G ; Khosravani M ; Adabi M
Source: Journal of Drug Delivery Science and Technology Published:2026

Abstract

Microglia are activated in response to an ischemic stroke, which is caused by a blockage of blood flow to the brain and results in neuronal damage. One potential therapeutic strategy for ischemic stroke is the inhibition of microglia-mediated neuroinflammation. As a biologic tumor necrosis factor (TNF) antagonist, etanercept (ETN) has demonstrated anti-inflammatory effects through inhibition of TNF-α. To the best of our knowledge, no prior research has reported the neuroprotective effects of ETN-loaded niosomes (ETN-Nio) in ischemic stroke; therefore, the present study aimed to address this gap. Male Wistar rats were randomly divided to five groups; a sham-operated group and four middle cerebral artery occlusion (MCAO) groups, including the MCAO without treatment, the MCAO with niosomes (Nio), the MCAO with ETN, and the MCAO with ETN-Nio. The niosomal nanoformulations were characterized, showing particle sizes of 131.6 ± 4.71 nm for Nio and 209 ± 5 nm for ETN-Nio (measured by DLS), with SPAN values of 0.941 ± 0.026 and 0.963 ± 0.014, respectively. The zeta potentials were −23.2 mV for Nio and −34.8 mV for ETN-Nio, while the encapsulation efficiency (EE%) and drug loading (DL%) for ETN-Nio were 55.26 ± 2.11% and 7.70 ± 0.29%, respectively. Treatment with ETN-Nio considerably decreased the infarction volume, brain edema, and neurological deficiency. Furthermore, the findings strongly support a neuroprotective reprogramming mechanism, as ETN-Nio significantly reduced the expression of NF-κB and C/EBPβ, reduced the M1 microglial marker (CD86) and increased the M2 marker (CD206), thereby promoting a shift of microglia toward the M2 phenotype. © 2026 Elsevier B.V.