Investigating VCAM-1 Targeted Nanoparticles and Annexin A1 Therapy using Dysfunctional-endothelium-on-a-chip

Atherosclerosis is an inflammation-driven disease of the arteries and one of the leading causes of global mortality. The initial pathological stage in atherosclerosis is dysfunctional endothelium (Dys-En), which results in loss of adherens-junctions between cells, thus enhancing permeability. Not only the enhanced permeability of Dys-En can be used as a nanoparticle targeting mechanism, but also the normalization and restoration of this phenomenon can be utilized as a potent anti-atherosclerotic therapy. This study aimed to recruit a robust biomicrofluidic model of Dys-En for 1) nanoparticle screening and 2) normalization assessments. The developed Dys-En-on-a-chip could successfully mimic the atherosclerotic flow condition, enhanced permeability, formation of actin stress fibers, and overexpression of vascular cell adhesion molecule 1 (VCAM-1), which are known as hallmarks of a Dys-En. The screening of VCAM-1 targeting nanoparticles with variable biophysicochemical properties showed that nanoparticle size plays the main role in nanoparticle targeting, and the design of nanoparticles in the range of 30-60 nm can highly increase their targeting to Dys-En. Moreover, treatment of Dys-En-on-a-chip with Annexin A1, as a novel pro-resolving mediator, resulted in restoration of adherens-junctions and normalization of the barrier integrity. This data validates the use of biomicrofluidic models for investigating treatment regimens with biologics and to identify optimal nanoparticle properties for effective atherosclerotic plaque targeting.