Atherosclerosis (AS) remains the primary pathological driver of cardiovascular diseases (CVDs), which account for ∼32% of global deaths. Early diagnosis of AS is critical for reducing mortality, but conventional diagnostic tools fail to dynamically assess oxidative stress—a key pathogenic factor in AS progression. Reactive oxygen species (ROS) are abnormally elevated in early AS plaques, making them a promising biomarker for early detection. However, existing ROS-responsive probes suffer from poor targeting specificity and insufficient sensitivity. RGD-targeted ROS-responsive dual-functional molecular probes, which integrate integrin-binding specificity and ROS-triggered signal activation, have emerged as a novel solution to these limitations. This review comprehensively summarizes the design principles, synthesis strategies, and preclinical evaluation (in vitro and in vivo) of RGD-targeted ROS-responsive probes for AS imaging. We focus on probe optimization strategies, including structural modification of RGD ligands, selection of ROS-sensitive moieties, and integration of fluorophores with optimal optical properties. Additionally, we discuss the current challenges in clinical translation and future directions for improving probe performance, with a dedicated focus on the potential applications of these probes in bioelectricity research—an emerging intersection of oxidative stress and vascular physiology. A systematic analysis of PubMed-listed literature (2020–2024, 77 articles; literature screening criteria: keywords including “atherosclerosis”, “RGD”, “ROS-responsive”, “molecular probe”, “targeted imaging”; excluding reviews, case reports, and studies with incomplete data) highlights the potential of these dual-functional probes to address unmet clinical needs in early AS diagnosis and bioelectricity-related research, providing insights for researchers in the fields of molecular imaging, cardiovascular medicine, and bioelectricity.
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