<p>Conventional drug-eluting balloons and stents continue to be associated with risks of in-stent restenosis and late-stage thrombosis, which may be attributed to severe endothelial injury during implantation and delayed re-endothelialization caused by early excessive release of anti-proliferative agents. Therefore, developing stent coatings that promote rapid endothelialization represents a promising strategy to reduce the risk of restenosis. Capitalizing on the distinctive features of the atherosclerotic microenvironment—particularly elevated reactive oxygen species (ROS) and acidic pH—we engineered a cascade drug-release coating by crosslinking oxidized sodium alginate with cystamine and incorporating atorvastatin (ATO)-loaded Cu-based layered double hydroxide (CuLDH*). This system operates through a sequential release mechanism: ROS-triggered degradation of the coating liberates CuLDH*, which subsequently decomposes under acidic conditions to release ATO and Cu²⁺ ions. The released Cu²⁺ further acts as a catalyst for generating nitric oxide (NO) from endogenous donors. This cascade strategy effectively circumvents the risk of cytotoxic peroxynitrite formation associated with direct NO donor application in high-ROS settings, while the pH-responsive CuLDH carrier prevents premature burst release of ATO, ensuring sustained and controlled drug elution. Therapeutically, the released Cu²⁺ ions catalyze the generation of NO from endogenous donors (e.g., S-nitrosothiols), while ATO and endogenously produced NO act synergistically to promote endothelial cell proliferation, migration, and functional restoration. This cascade drug-release coating enables the precise delivery of ATO and Cu²⁺ to cooperatively enhance endogenous NO bioavailability. This work provides a novel strategy for stent coating design, featuring a smart design that enables rapid re-endothelialization through programmed drug release.</p>