mPEG@ELA-11 Alleviates Atherosclerosis via AKT-ER Stress-Mediated Macrophage Modulation

<b>Objective:</b> This study explores the role of methoxy polyethylene glycol@Elabela-11 (mPEG@ELA-11), a pH-responsive ELA-11 conjugate, in modulating macrophage function and attenuating atherosclerosis, focusing on the protein kinase B (AKT)-mediated endoplasmic reticulum (ER) stress pathway as a molecular target. <b>Impact Statement:</b> We reveal that ELA-11 alleviates atherosclerosis by suppressing macrophage foam cell formation, M1 polarization, and apoptosis via the AKT-ER stress pathway. We also develop mPEG@ELA-11, a novel pH-responsive nanocarrier, to enhance targeted drug delivery and therapeutic efficacy, offering a breakthrough for peptide-based cardiovascular nanomedicine. <b>Introduction:</b> Atherosclerosis, driven by macrophage dysfunction and lipid accumulation, is a major global killer. ELA-11, a fragment of Elabela peptide, shows cardiovascular protective effects, but its role in atherosclerosis and optimal delivery remain unstudied. <b>Methods:</b> Elabela mRNA (APELA) expression was analyzed in human carotid atherosclerotic plaques using real-time quantitative PCR analysis, and serum ELA levels were quantified via enzyme-linked immunosorbent assay in patients with carotid stenosis. In vitro studies on RAW264.7 macrophages evaluated mPEG@ELA-11 effects on oxidized low-density lipoprotein-induced foam cell formation, polarization, and apoptosis. In vivo efficacy was tested in ApoE^-/- mice, comparing mPEG@ELA-11 with free ELA-11, and its pH-responsive release mechanism was characterized. <b>Results:</b> APELA was down-regulated in human atherosclerotic plaques, especially unstable lesions. mPEG@ELA-11 suppressed foam cell formation, M1 polarization, and apoptosis by inhibiting the AKT-ER stress pathway in vitro. In mice, it reduced plaque area more effectively than free ELA-11 attributed to pH-triggered release. <b>Conclusion:</b> The pH-responsive mPEG@ELA-11 alleviates atherosclerosis by modulating macrophages via the AKT-ER stress pathway, with favorable targeting and safety, representing a promising targeted peptide nanomedicine for atherosclerosis.