Zhao Jing, Jia Fan, Li Jian, Tao Ye-Cheng, Hu Jia-Yi, Ren Ke-Feng, Ji Jian, Fu Jia-Yin, Fu Guo-Sheng, Huang He
Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine, Engineering Research Center for Cardiovascular Innovative Devices of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China.
ACS Nano. 2025 Jun 17;19(23):21757-21774. doi: 10.1021/acsnano.5c05477. Epub 2025 Jun 2.
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. and 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.
药物涂层球囊在冠状动脉狭窄介入治疗中不断发展，但常导致创伤性血管损伤，引发晚期再狭窄。这一过程中的一个关键病理事件是内皮屏障完整性的早期破坏，从而引发炎症和增生。然而，目前缺乏能迅速恢复内皮完整性的有效治疗策略。在此，我们确定消除过量活性氧（ROS）是加强细胞间紧密连接（TJ）和恢复内皮屏障功能的关键机制。因此，我们提出一种可喷涂的、对ROS有响应的水凝胶涂层OA@G-NO/B-EC，用于血管球囊，旨在减轻晚期再狭窄。这种水凝胶通过超声喷涂精确制备，包含一种带有可逆苯基硼酸酯的咖啡酸前药（B-EC）和一种大分子一氧化氮（NO）供体（G-NO），二者均通过席夫碱化学与多巴胺修饰的氧化葡聚糖（OA）动态自交联。双重动态共价键使水凝胶能够在病变部位响应ROS积累而逐渐分解，提供可控的按需治疗作用。草药抗氧化剂咖啡酸盐的持续释放有效清除ROS，挽救TJ完整性并减轻炎症。这种有利的微环境进一步增强内源性NO生成和外源性NO递送，促进内皮细胞增殖和迁移。此外，这种水凝胶对动脉壁的强大粘附力确保了足够的药物保留和递送。RNA测序分析支持的 和 结果有力地证明了该水凝胶增强血管愈合和预防再狭窄的能力。该系统在各种生物医学材料和装置的表面工程方面具有广阔潜力，推动局部药物递送。
