Sprayable Reactive Oxygen Species-Responsive Hydrogel Coatings Restore Endothelial Barrier Integrity for Functional Vascular Healing

Abstract

Drug-coated balloons are advancing in coronary interventional therapy for stenosis but often cause traumatic vascular injury, leading to late-stage restenosis. A critical pathological event in this process is the early disruption of the endothelial barrier integrity, which triggers inflammation and hyperplasia. However, effective therapeutic strategies to promptly restore endothelial integrity are lacking. Here, we identify the elimination of excess reactive oxygen species (ROS) as a key mechanism for reinforcing intercellular tight junctions (TJs) and restoring the endothelial barrier function. We thus propose a sprayable, ROS-responsive hydrogel coating, OA@G-NO/B-EC, for vascular balloons designed to mitigate late-stage restenosis. This hydrogel, precisely fabricated via ultrasonic spraying, comprises a reversible phenylboronic ester-bearing caffeate prodrug (B-EC) and a macromolecular nitric oxide (NO) donor (G-NO), both dynamically self-cross-linked with dopamine-modified oxidized dextran (OA) through Schiff base chemistry. The dual dynamic covalent linkages enable the hydrogel to gradually disintegrate in response to ROS accumulation at lesion sites, providing controlled, on-demand therapeutic action. Sustained release of herbal antioxidant caffeates effectively scavenges ROS, rescuing TJ integrity and attenuating inflammation. This favorable microenvironment further enhances both endogenous NO production and exogenous NO delivery, facilitating endothelial proliferation and migration. Moreover, this hydrogel's robust adhesion to the arterial wall ensures sufficient drug retention and delivery. In vitro and in vivo results, supported by RNA sequencing analysis, strongly demonstrate the hydrogel's enhanced capacity for vascular healing and restenosis prevention. This system holds broad potential for surface engineering across diverse biomedical materials and devices, advancing localized drug delivery.

Keywords: drug-coated balloons; endothelial barrier; hydrogel coating; nitric oxide (NO); reactive oxygen species (ROS); tight junctions (TJs); vascular restenosis.