A Spatially Cued, Sequentially Activated DNA Nanodevice for Atherosclerosis Theranostics via Precise Targeting of Lesional Macrophages

Atherosclerosis (AS), a major contributor to cardiovascular diseases, involves macrophages as a pivotal driver of its pathogenesis. Developing macrophage-targeted therapies that effectively mitigate AS while minimizing systemic effects remains a challenge. Here, we present an intelligent theranostic method for AS using an <u>a</u>ccurate <u>s</u>patiotemporal-speci<u>fi</u>cally respo<u>n</u>sive <u>D</u>N<u>A</u> nanostru<u>c</u>t<u>ure</u> (ASfindaCure). To precisely target atherogenic macrophages, we leverage a spatially distinctive expression pattern comprising a membrane protein (SIRPα), a microenvironmental cue (thrombin), and two intracellular biomarkers (APE1 and microRNA-155). By harnessing structural and dynamic DNA nanotechnologies, ASfindaCure temporally orchestrates recognition events for these spatially distributed biomarkers via programmable reaction cascades. Utilizing fluorescence and photoacoustic dual-modality imaging, we demonstrate that ASfindaCure accurately targets AS-causing macrophages, providing a noninvasive imaging method to assess AS progression. In both cellular and mouse models, ASfindaCure demonstrated effective delivery of microRNA-33 antisense oligonucleotides to targeted cells, significantly mitigating plaque progression and inflammation. This intelligent theranostic nanoplatform holds great promise for the development of next-generation treatments for AS and has potential applications in other disease conditions.