<p>Intraluminal drug coated devices, such as paclitaxel (PTX)-coated balloons, are commonly used to treat arterial occlusive diseases caused by atherosclerosis. However, their efficacy is limited by drug loss, poor drug retention, insufficient penetration and high costs. Nanoparticles with molecular targeting capabilities offer a promising solution to these challenges. Collagen hybridizing peptide (CHP) specifically binds to degraded collagen in atherosclerotic plaques, enabling precise molecular imaging and targeted therapy. In this study, we demonstrated that collagen degradation was significantly elevated in atherosclerotic plaques and could be effectively identified by CHP in both atherosclerosis patients and mice models. Using the emerging copper-free click chemistry reaction, we functionalized the widely used albumin-based indocyanine green nanoparticles and albumin-bound paclitaxel nanoparticles with CHP, developing a targeted nanoplatform for molecular imaging and therapy. In vivo photoacoustic (PA) imaging and ex vivo fluorescence (FL) imaging revealed significantly enhanced PA and FL signals in carotid artery and aorta plaques with CHP functionalized nanoparticles engaging. Furthermore, therapeutic evaluations showed that CHP significantly improved the plaque-targeting capability of albumin-bound paclitaxel nanoparticles, thereby enhancing their therapeutic efficacy against atherosclerotic plaques. These findings highlighted CHP-functionalized albumin nanoparticles as a promising strategy for precise and effective atherosclerosis molecular imaging and treatment.</p> Graphical Abstract <p></p>