Size, shape, and flexibility influence nanoparticle transport across brain endothelium under flow

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Neuroscience

Background:

• Nanoparticle-based therapies show promise for various diseases but face challenges in treating brain disorders.
• Limited nanoparticle penetration across the blood-brain barrier (BBB) is a major hurdle for brain-targeted therapies.
• Current strategies focus on affinity-based targeting, with less understanding of physical parameter impacts.

Purpose of the Study:

• To investigate how nanoparticle physical properties (size, shape, flexibility) affect their interaction with and transport across the BBB.
• To utilize a three-dimensional human BBB microfluidic model (μHuB) for studying nanoparticle-BBB dynamics.
• To determine if optimizing physical parameters can improve nanoparticle delivery to the brain.

Main Methods:

• Utilized a three-dimensional human blood-brain barrier microfluidic model (μHuB).
• Investigated nanoparticle association with the brain endothelium and transport across the BBB.
• Systematically varied nanoparticle size, shape (spherical vs. rod), and flexibility (hard vs. soft).

Main Results:

• Nanoparticle association with the endothelium was influenced by physical characteristics: hard > soft, small > large, spherical > rod-shaped.
• BBB transport showed a non-monotonic size dependence (200nm spheres > 100nm, 500nm spheres).
• Rod-shaped and soft nanoparticles showed enhanced transport when normalized for endothelial association.

Conclusions:

• Nanoparticle physical properties critically impact BBB interaction and transport.
• Tuning size, shape, and flexibility offers a strategy to enhance brain-targeted nanoparticle delivery.
• Further optimization of these parameters holds potential for advancing nanoparticle therapies for neurological diseases.