Duplex Responsive Nanoplatform with Cascade Targeting for Atherosclerosis Photoacoustic Diagnosis and Multichannel Combination Therapy

Abstract The culprits of atherosclerosis are endothelial damage, local disorders of lipid metabolism, and progressive inflammation. Early atherosclerosis is typically difficult to diagnose in time due to the lack of obvious symptoms, thus missing the best period of treatment. In this work, a π‐conjugated polymer (PMeTPP‐MBT) based on 3,6‐bis(4‐methylthiophen‐2‐yl)‐2,5‐bis(2‐octyldodecyl)pyrrolo[3,4‐c]pyrrole‐1,4(2H,5H)‐dione is designed as a novel photoacoustic contrast agent. On this basis, an intelligent responsive theranostic nanoplatform (PA/ASePSD) combining astaxanthin and SS‐31 peptide and loading with PMeTPP‐MBT is developed. The high affinity between the dextran shell with the broken endothelial surface VCAM‐1 and CD44 confers active targeting of PA/ASePSD to atherosclerotic lesions. High levels of ROS in the acidic plaque microenvironment act as an intelligent cascade switch to achieve controlled release of astaxanthin, SS‐31 peptide, and PMeTPP‐MBT for non‐invasive photoacoustic diagnosis, as well as plaque inhibition mediated by anti‐inflammation and multichannel regulation (including ABCA1, ABCG1, CD36, and LOX‐1) of lipid metabolism. Both in vitro and in vivo evaluations confirm the impressive anti‐atherosclerotic capability and the accurate photoacoustic diagnosis of PA/ASePSD nanoparticles, thus promising a candidate for early‐stage atherosclerosis theranostics.