# Shear Stress Targeted Delivery of Nitroglycerin to Brain Collaterals Improves Ischaemic Stroke Outcome

## TL;DR

A new method uses shear-activated nanoparticles to deliver nitroglycerin to brain collateral vessels during stroke, improving blood flow and outcomes without side effects.

## Contribution

A novel shear-activated nanoparticle system for targeted nitroglycerin delivery to high-shear collateral vessels in ischaemic stroke.

## Key findings

- NG-NPAs increased penumbral perfusion and reduced infarct volume in rat stroke models.
- NG-NPAs avoided systemic hypotension and other side effects of conventional nitrate administration.
- Free NG at higher doses failed to enhance collateral flow and caused blood pressure drops.

## Abstract

In patients with ischaemic stroke, retrograde perfusion of the penumbra by leptomeningeal collateral vessels (LMCs) strongly predicts clinical outcome, suggesting that enhancing LMC flow can offer a novel therapeutic approach. Using in vivo measurements and computational modelling it is shown that LMCs experience elevated fluid shear stress that is significantly higher than that in other blood vessels during ischaemic stroke in rats and humans. We exploit this to selectively enhance flow in LMCs using shear‐activated nanoparticle aggregates carrying the vasodilator nitroglycerin (NG‐NPAs) that specifically release drug in regions of vessels with high wall shear stress (≥100 dyne cm−2). NG‐NPAs significantly increased LMC‐mediated penumbral perfusion, decreased infarct volume, and reduced neurological deficit without altering systemic blood pressure in a rat ischaemic stroke model. NG‐NPAs also avoided common side effects of systemic nitrate administration, such as systemic hypotension, cerebral vascular steal, cortical vein dilation, or intracranial pressure elevation. Systemic administration of free NG at the maximal tolerated dose, which is ten times higher than the dose of NG used in the NG‐NPAs, do not enhance LMC perfusion and dropped blood pressure. Thus, packaging NG within shear‐activated NPAs can potentially enable this widely available vasodilator to become a highly effective therapeutic for ischaemic stroke.

Shear‐activated nanoparticles carrying nitroglycerin selectively target high‐shear stress collateral vessels during ischaemic stroke, enhancing blood flow to at‐risk brain without systemic side effects. This novel approach significantly improves outcomes in animal models, outperforming conventional nitroglycerin delivery. The findings suggest a promising therapeutic strategy that repurposes a common vasodilator for precise, stroke‐specific intervention.