Fredman, G.Kamaly, NazilaSpolitu, S.Milton, J.Ghorpade, D.Chiasson, R.Kuriakose, G.Perretti, M.Farokhzad, OmidTabas, I.2016-10-202015Fredman G., N. Kamaly, S. Spolitu, J. Milton, D. Ghorpade, R. Chiasson, G. Kuriakose, M. Perretti, O. Farokhzad, and I. Tabas. 2015. “Targeted Nanoparticles Containing the Proresolving Peptide Ac2-26 Protect Against Advanced Atherosclerosis in Hypercholesterolemic Mice.” Science Translational Medicine 7 (275). doi:10.1126/scitranslmed.aaa1065.1946-6234http://nrs.harvard.edu/urn-3:HUL.InstRepos:29058532Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1. The proresolving actions of annexin A1, which are mediated through its receptor N-formyl peptide receptor 2 (FPR2/ALX), can be mimicked by an amino-terminal peptide encompassing amino acids 2–26 (Ac2-26). Collagen IV (Col IV)–targeted nanoparticles (NPs) containing Ac2-26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr−/− mice. When administered to mice with preexisting lesions, Col IV–Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions (which was associated with a decrease in lesional collagenase activity), suppression of oxidative stress, and a decrease in plaque necrosis. In mice lacking FPR2/ALX in myeloid cells, these improvements were not seen. Thus, administration of a resolution-mediating peptide in a targeted NP activates its receptor on myeloid cells to stabilize advanced atherosclerotic lesions. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy.en-USJournal Article2016-10-2010.1126/scitranslmed.aaa1065