Cardiovascular diseases (CVDs) are the foremost cause of mortality worldwide, with incidence and mortality rates persistently climbing despite extensive research efforts. Innovative therapeutic approaches are still needed to extend patients' lives and preserve their health. In the present study, novel supramolecular nanomedicine with both nitric oxide (NO) and antioxidant releasing ability was developed to enhance therapeutic efficacy against vascular injuries. Utilizing α-cyclodextrin (α-CD) as a host molecule, the nanomedicine aims to achieve site-specific delivery via targeting peptide rendered selective accumulation. By scavenging ROS and amplifying NO's regulatory effects, the nanomedicine readily restored vascular homeostasis, in both acute and chronic CVDs. It served as a promising solution to overcome the challenges associated with NO-based therapies and may inspire future research studies on new therapies for CVDs.