Vulnerable atherosclerotic plaques are responsible for most cardiovascular diseases (CVDs). Folate receptor (FR) positive activated macrophages were thought to be a prominent component in the development of vulnerable plaque. The objective of this study is to develop folate conjugated two-dimensional (2D) Pd@Au nanomaterials (Pd@Au-PEG-FA) for targeted multimodal imaging of the FRs in advanced atherosclerotic plaques. Pharmacokinetic and imaging studies (single photon emission computed tomography (SPECT), computed tomography (CT) and photoacoustic (PA) imaging) were performed to confirm the prolonged blood half-life and enrichment of radioactivity in atherosclerotic plaques. Strong signals were detected in vivo with SPECT, CT and PA imaging in heavy atherosclerotic plaques, which were significantly higher than those of the normal aortas after injection of Pd@Au-PEG-FA. Blocking studies with preinjection of excess folic acid (FA) could effectively reduce the targeting ability of Pd@Au-PEG-FA in atherosclerotic plaques, further demonstrating the specific binding of Pd@Au-PEG-FA for plaque lesions. Histopathological characterization revealed that the signal of probe was in accordance with the high-risk plaques. In summary, the Pd@Au-PEG-FA has favorable pharmacokinetic properties and provides a valuable approach for detecting high-risk plaques in the presence of FRs in atherosclerotic plaques.