Hyaluronic-acid (HA)-coated LOX-1-specific siRNA-condensed cell-penetrating peptide (CPP) nanocomplexes (NCs) were developed for targeted gene delivery to macrophages and suppression of lipid accumulation. The HA coating facilitated the accumulation of nanoparticles at leaky endothelium overexpressing CD44 receptors and was further degraded by hyaluronidase (HAase) intraplaques for exposing the naked CPP NCs and achieving the ultimate location into macrophages. The surface coating of HA was verified by the increased particle size, inverted zeta potential, and TEM images. The targeting mechanism was studied on the established injured endothelium-macrophage coculture system, which revealed that modification of higher molecular weight HA and higher HA coating density on NCs, termed as NPs-3, improved the intracellular uptake of nanoparticles by macrophages. Macrophages internalized NCs via caveolae-mediated endocytosis pathway. Moreover, NPs-3 exhibited better cellular drug efficacy in preventing macrophage-derived foam cell formation than other preparations. Compared with NCs, HA decoration showed enhanced atherosclerotic-lesion-targeting efficiency, proven by results from ex vivo imaging. Furthermore, atheroprotective efficacy study in apoE-deficient mice showed that NPs-3 had the best potent efficacy, which was demonstrated by the fewest atherosclerotic lesions sizes and lipid accumulation, the lowest macrophage infiltration, and the lowest expression of monocyte chemoattractant protein-1 (MCP-1), respectively. Collectively, the HA-coated CPP NCs were promising nanocarriers for efficient macrophage-targeted gene delivery and antiatherogenic therapy.