A foam cell-targeted lipophagy restoration strategy stabilizes vulnerable atherosclerotic plaques

Despite advances in therapies for atherosclerosis, the limited efficacy in reversing vulnerable atherosclerotic plaques remains a significant challenge in translational cardiovascular research. We developed OPN-HMCN@MLT, a targeted nanoplatform combining melatonin (MLT) with an osteopontin (OPN)-binding peptide and hyaluronic acid–modified mesoporous carbon. By exploiting the acidic, HAase-overexpressing, and OPN-enriched microenvironment of vulnerable plaques, this system enables cascade-responsive drug release triggered sequentially by OPN recognition, HA degradation, and acidic pH. This system enables precise plaque targeting and label-free photoacoustic (PA) imaging, exploiting the intrinsic imaging capacity of carbon carriers while enhancing MLT's bioactivity. Elevated OPN expression in foam cells facilitates selective retention of OPN-HMCN@MLT in vulnerable lesions, resulting in enhanced plaque-associated PA signals. In vivo studies demonstrate that OPN-HMCN@MLT not only suppresses plaque progression but also promotes regression of established lesions, accompanied by reduced foam cell accumulation, improved lipid metabolic reprogramming, and enhanced plaque stability, without detectable systemic toxicity. By functionally coupling targeted lipophagy restoration with supportive molecular imaging at the pathological substrate level, this work establishes a therapy-centered nanomedicine strategy that enables precision intervention and longitudinal monitoring, offering strong translational potential for the management of advanced atherosclerosis. • A foam cell–targeted nanoplatform (OPN-HMCN@MLT) achieves precise theranostics of vulnerable plaques. • Integrates melatonin delivery and label-free photoacoustic imaging via mesoporous carbon carriers. • Restores lipophagy and promotes cholesterol efflux through PPARα/CPT1A/ACOX-1 and PPARγ/ABCA1/G1 axes. • Effectively reverses advanced atherosclerotic plaques without detectable systemic toxicity. • Provides a translational nanotheranostic strategy for lipophagy-driven plaque regression and stabilization.