Issue 7, 2023

Mechanobiological modulation of blood–brain barrier permeability by laser stimulation of endothelial-targeted nanoparticles

Abstract

The blood–brain barrier (BBB) maintains an optimal environment for brain homeostasis but excludes most therapeutics from entering the brain. Strategies that reversibly increase BBB permeability are essential for treating brain diseases and are the focus of significant preclinical and translational interest. Picosecond laser excitation of tight junction-targeted gold nanoparticles (AuNPs) generates a nanoscale mechanical perturbation and induces a graded and reversible increase in BBB permeability (OptoBBB). Here we advanced this technique by showing that targeting endothelial glycoproteins leads to >10-fold higher targeting efficiency than targeting tight junctions both in vitro and in vivo. With both tight-junction and glycoprotein targeting, we demonstrate that OptoBBB is associated with a transient elevation and propagation of Ca2+, actin polymerization, and phosphorylation of ERK1/2 (extracellular signal-regulated protein kinase). These collectively activate the cytoskeleton resulting in increased paracellular permeability. The Ca2+ response involves internal Ca2+ depletion and Ca2+ influx with contributions from mechanosensitive ion channels (TRPV4, Piezo1). We provide insight into how the excitation of tight junction protein (JAM-A)-targeted and endothelial (glycocalyx)-targeted AuNPs leads to similar mechanobiological modulation of BBB permeability while targeting the glycocalyx significantly improves the nanoparticle accumulation in the brain. The results will be critical for guiding the future development of this technology for brain disease treatment.

Graphical abstract: Mechanobiological modulation of blood–brain barrier permeability by laser stimulation of endothelial-targeted nanoparticles

Supplementary files

Article information

Article type
Paper
Submitted
14 9 2022
Accepted
16 1 2023
First published
17 1 2023

Nanoscale, 2023,15, 3387-3397

Mechanobiological modulation of blood–brain barrier permeability by laser stimulation of endothelial-targeted nanoparticles

X. Li, Q. Cai, B. A. Wilson, H. Fan, H. Dave, M. Giannotta, R. Bachoo and Z. Qin, Nanoscale, 2023, 15, 3387 DOI: 10.1039/D2NR05062E

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements