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Serum neurofilament light chain (NfL) is increasingly being used as a biomarker to quantitate severity and predict outcomes in acute ischemic stroke (AIS) trials. However, there are limited preclinical studies that employ NfL to optimize the dosing strategy for novel drugs and modalities. AB126 is an investigational human neural small extracellular vesicle (sEV) with robust neuroprotective and anti-inflammatory properties and recently gained FDA Investigational New Drug clearance to enter clinical trials for AIS. The goals of this study were to 1) investigate the relationship between serum NfL and other indicators of stroke severity in a rat model of AIS and 2) compare the therapeutic effect of three AB126 dose regimens on AIS outcome including serum NfL levels. Neural stem cell culture media underwent tangential flow filtration and chromatography to separate and concentrate the sEV, followed by nanoparticle tracking analysis. Transient intraluminal middle cerebral artery occlusion (tMCAO) was induced in rats at the origin of the middle cerebral artery. After 150min, the filament was removed to restore perfusion. For the intravenous AB126 (2.7e11 particles/kg) treatment study, rats were divided into four groups: untreated, 1 dose given 4hr post-tMCAO, 2 doses given 24 and 48hr post-tMCAO, or 3 doses given 4, 24, and 48hr post-tMCAO (n=7-20/group). Body weight (daily), neurological deficit (Days -1, 0, 1, and 3), and serum NfL (Days 1-3) were collected. Infarct size was measured on Day 3. Study results showed that Day 3 serum NfL was positively correlated with Day 3 weight loss (R=0.79, p=<0.0001) and infarct volume (R=0.76, p=<0.0001) in untreated animals. Furthermore, all three AB126 dose regimens significantly (p<0.05) reduced infarct volume compared to untreated controls while the 3-dose regimen significantly (p<0.05) improved neurologic deficit between Day 1 and Day 3. While all AB126 dose regimens reduced mean serum NfL, the 3-dose regimen generated the most robust response with significantly (p<0.05) reduced NfL on Day 2 compared to untreated animals. These results demonstrate the utility of serum NfL as a biomarker for optimizing therapeutic strategies for AIS. Our Phase 1b/2a AIS clinical study will evaluate changes in serum NfL pre- and post-AB126 administration.