Abstract

In-stent restenosis (ISR), a chronic vascular proliferative disorder, poses significant clinical challenges due to impaired endothelial repair, suboptimal long-term outcomes of interventional therapies, and complications associated with current preventive strategies. Although gene therapy offers a promising approach for ISR management, its clinical translation is hindered by the scarcity of innovative gene-based drugs and the lack of efficient delivery systems. Here, we identify carbonic anhydrase 1 (CA1) as a potential target in regulating endothelial cell survival, regeneration, and inflammatory responses. We then engineered plant-derived exosome-like nanoparticles (CLENs) to encapsulate CA1-siRNA, enabling targeted delivery and enhanced stability. CLENs (siRNA) exhibit prolonged circulation and precise accumulation at aortic lesions, effectively reducing ISR rates. Mechanistically, this therapeutic approach alleviates endothelial inflammatory activation by suppressing the NF-κB and TNF signaling pathways and downregulating PADI2 expression, while also demonstrating favorable biosafety. Our study presents a novel plant-derived nano-delivery system based on purely natural components for early ISR intervention, which demonstrates both therapeutic efficacy and an absence of adverse effects.