Engineered Pericyte-Targeted Extracellular Vesicles Protect Against Hypoperfusion-Induced Cognitive Impairment and...

Pericyte dysfunction is an early hallmark of vascular cognitive impairment (VCI), yet targeted therapies remain limited. Here, we develop a bio-orthogonal approach to engineer extracellular vesicles (EVs) functionalized with cyclic NGR (cNGR) peptides for selective pericytes targeting. The resulting cNGR-EVs demonstrated efficient targeting of CD13-expressing brain pericytes both in vitro and in vivo. In a mouse model of chronic cerebral hypoperfusion (bilateral common carotid artery stenosis, BCAS), cNGR-EVs preserved pericyte contractility, protected against cerebral hypoperfusion, reduced blood-brain barrier leakage, and attenuated demyelination, leading to improved cognitive performance. Single-cell RNA sequencing further revealed that cNGR-EVs attenuated the majority of BCAS-induced transcriptional changes in pericytes, partially preserved pericyte-mediated intercellular communication, and normalized downstream neuronal and glial gene expression profiles. These findings underscore cNGR-EVs as a pericyte-targeted strategy capable of stabilizing the neurovascular unit, maintaining pericyte function, and preventing cognitive decline and myelin loss, highlighting pericytes as a promising therapeutic target in early VCI treatment.