Atherosclerosis is a leading cause of cardiovascular diseases worldwide. Neutrophil elastase, a key protease secreted by neutrophils, contributes significantly to atherosclerosis by degrading the extracellular matrix and destabilizing the fibrous cap of plaques. However, current detection methods for neutrophil elastase lack the ability to monitor its dynamic changes within plaques in a non-invasive and real-time manner. To overcome this limitation, we develop a neutrophil elastase-activated semiconductor polymer nanoprobe with high selectivity, sensitivity, and resistance to interference. We successfully establish a calibration curve correlating the in vivo photoacoustic signal ratio with neutrophil elastase concentration, enabling quantification of intraplaque neutrophil elastase levels. Importantly, we introduce a vulnerability index to assess plaque instability, allowing the nanoprobe to predict the adverse effects of inflammatory responses on the risk of plaque rupture in ApoE-/- male mice. Additionally, the nanoprobe can visualize dynamic changes in neutrophil elastase during intimal hyperplasia under inflammatory conditions. In conclusion, this nanoprobe provides a tool for elucidating the role of neutrophil elastase in cardiovascular disease progression.