On August 27, 2026, the famous top chemistryjournalJournal of the American Chemical Societyonline published the research from the group of Professor Liang Gaolin at the National Key Laboratory of Digital Medical Engineering/School of Biological Science and Medical Engineeringof Southeast University. The paper is entitled Noninvasive Photoacoustic and Fluorescence Bimodality Imaging Differentiation of Vulnerable Atherosclerotic Plaques at Different Stages. In this study, a smart molecular probe RGD-IR-Dimer with integrin αvβ3-targeting and matrix metalloproteinase-8 (MMP-8)-responsive properties was constructed, enabling non invasive photoacoustic/fluorescence bimodal differential imaging of vulnerable atherosclerotic plaques at distinct progression stages (J. Am. Chem. Soc. 2026, DOI: https://doi.org/10.1021/jacs.6c13308).
Vulnerable atherosclerotic plaques constitute the major pathological basis triggering acute cardiovascular events. Although conventional angiography can identify plaques, it fails to discriminate their progression stages (early versus late), leaving clinical practice without effective imaging modalities for early detection and intervention of high-risk vulnerable plaques. To address this bottleneck, Professor Gaolin Liang’s group designed the integrin αvβ3-targeting, MMP-8-responsive smart molecular probe RGD-IR-Dimer (Figure a). This molecule adopts a cyclic dimeric architecture, incorporating the cyclic RGD peptide targeting moiety that recognizes the neovascular biomarker αvβ3, a peptide substrate specifically cleavable by MMP-8 (a biomarker associated with vulnerable plaques), and the near infrared fluorescent/photoacoustic imaging dye IR780. The working mechanism of the probe is illustrated in Figure b. Following intravenous injection, αvβ3-mediated active targeting drives selective accumulation of the probe within plaque lesions. Elevated local concentration triggers its self assembly into nanofibers and elicits the aggregation-caused quenching (ACQ) effect, which quenches fluorescence while “turning on” photoacoustic signals. At the early stage of plaque progression, neovessels exhibit high αvβ3 expression but low MMP-8 expression.Accordingly, the probe presents the feature of “photoacoustic signal on and fluorescence-off”. At the late plaque stage, foam cells secrete large quantities of MMP-8. Enzymatic cleavage disassembles the probe, attenuating photoacoustic signals and restoring fluorescence signals, thus realizing temporal conversion between the two bimodal signals. As such, early plaques are dominated by photoacoustic signals, whereas late plaques exhibit a “photoacoustic-to-fluorescence” signal switch. The distinction between these signal patterns permits effective staging of plaques. At the cellular level, bEnd.3 endothelial cells with high αvβ3 expression were used to mimic the microenvironment of early neovessels, while LDL-induced RAW264.7 macrophage-derived foam cells recapitulated the status of robust MMP-8 secretion in late-stage plaques. These two cellular models recapitulated the representative temporal molecular profiles (high αvβ3/low MMP-8 and low αvβ3/high MMP-8), systematically verifying the probe’s specific responsiveness to microenvironments with differential biomarker levels across plaque stages. Animal experiments further validated the capacity of the probe to produce the “photoacoustic-to-fluorescence” signal conversion in late-stage plaques. Collectively, by taking clever advantage of the temporally differential expression of αvβ3 and MMP-8 throughout plaque progression, this study achieves intelligent discrimination of plaques at different stages using a single probe. It overcomes the limitation of conventional imaging modalities that cannot assess plaque progression stages, and offers a promising new strategy for detection and early intervention of high-risk plaques.
Dr. Qiaochu Jiang of School of Biological Science and Medical Engineering andDr. PenghaoZhenof Medical Schoolof Southeast Universityare co-first authors of this paper. Professor Gaolin Liang, Chair Professor of Southeast University and the Deputy Director of the National Key Laboratory of Digital Medical Engineering, is the corresponding author. This research was supported by the National Natural Science Foundation of China,the Natural Science Foundation of Jiangsu Province, and Jiangsu Shuang Chuang Team.
Articlelinkage: https://doi.org/10.1021/jacs.6c13308
