Beyond Lipid Lowering: Targeting lncRNAs as a Novel Therapeutic Strategy for Vascular Wall Defense in Atherosclerosis

Atherosclerosis remains the primary pathological foundation for severe cardiovascular events. Although guideline-directed medical therapy-particularly statins, cholesterol absorption inhibitors, and PCSK9 inhibitors-effectively reduces circulating low-density lipoprotein cholesterol (LDL-C), the risk of major adverse cardiovascular events driven by vulnerable plaque rupture persists. Conventional therapies alleviate systemic lipid burdens but fail to adequately reverse localized immune dysregulation and structural damage in situ within the vascular wall. Consequently, cardiovascular precision medicine is shifting towards actively rebuilding the vascular wall defense system. Leveraging their high tissue specificity and epigenetic regulatory capabilities, long non-coding RNAs (lncRNAs) serve as critical hubs for vascular homeostasis, representing novel therapeutic targets for reconstructing this defense network. This review summarizes how aberrant lncRNAs disrupt endothelial barriers, drive vascular smooth muscle cell dedifferentiation, and induce macrophage dyshomeostasis, while emphasizing the necessity of rigorously validating competing endogenous RNA mechanisms. To actualize in situ intervention, we highlight advances in nucleic acid therapeutics (antisense oligonucleotides and small interfering RNAs) and sophisticated nanodelivery systems-including biomimetic coatings and active targeting-that overcome extrahepatic delivery barriers for deep-plaque penetration. Finally, we address critical translational hurdles (interspecies conservation, off-target toxicity), evaluate circulating lncRNA biomarkers, and propose integrating lncRNA interventions with existing pharmacotherapies. Empowered by artificial intelligence for rational target discovery and theranostic nanoplatforms, lncRNA-directed therapies promise to mitigate persistent plaque vulnerability and advance cardiovascular precision medicine.