Plaque Macrophage‐Targeting Nanosystems with Cooperative Co‐Regulation of ROS and TRAF6 for Stabilization of Atherosclerotic Plaques

Abstract Chronic inflammatory microenvironment is the predominant milieu that promotes the progression of atherosclerosis (AS). However, targeted regulation of the chronic proinflammatory milieu still needs to be improved. In this study, macrophage‐targeting nanosystems composed of 37pA peptide embedded–Pt lipid nanoparticles (37pA‐PtLNP) and tumor necrosis factor‐associated factor 6 (TRAF6) inhibitor (6877002)‐loaded poly(ε‐caprolactone)‐b‐polyethylene glycol‐b‐poly(ε‐caprolactone) (PCEC) are constructed with 37pA peptide embedded–lipid coating (37pA‐LNP/6877002), to stabilize atherosclerotic lesions. The cooperative regulation effects of these nanosystems in achieving reactive oxygen species (ROS) scavenging and inflammatory signaling inhibition are investigated. 37pA‐PtLNP effectively scavenges several ROS, however, also promotes the expression of iNOS. The introduction of 37pA‐LNP/6877002 inhibits the activities of TRAF6, a downstream intracellular factor of the CD40L‐CD40‐TRAF6 axis, to decrease the proportion of the proinflammatory M1 macrophage phenotype, which is further downregulated by combined treatment with 37pA‐PtLNP. The combination of 37pA‐PtLNP and 37pA‐LNP/6877002 not only counteracts 37pA‐PtLNP–induced iNOS upregulation but also alleviates the chronic inflammatory microenvironment by reducing the expression of proinflammatory cytokines and chemokines. The anti‐AS efficacy in vivo on ApoE^−/− mice further demonstrates that the combination of 37pA‐PtLNP and 37pA‐LNP/6877002 targetedly modulates the atherosclerotic plaque microenvironment, achieving stabilization of lesions with minimal progression. This study provides a promising strategy for AS management.