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Reprogramming macrophages to a restorative phenotype in cancer or autoimmune diseases can stop their cancer\u2010promoting activity or trigger anti\u2010inflammatory immunity. Glycans have emerged as key components for immunity as they are involved in many pathophysiological disorders. Previous studies have demonstrated that supraphysiological amounts of mannose (Man) or sialic acid (Sia) can inhibit tumor growth and stimulate differentiation of regulatory T cells. Man is known to affect glucose metabolism in glycolysis by competing for the same intracellular transporters and affecting macrophage polarization, whereas Sia alters macrophage differentiation via signaling through Siglec\u20101. Herein, this work describes a macrophage targeting platform using gold nanoparticles (GNPs) functionalized with Man and Sia monosaccharides which exhibit high liver tropism. A single dose of glyco\u2010GNPs can convert macrophages to a restorative phenotype in two completely different immune environments. Man promotes tumor\u2010associated macrophages toward an antitumorigenic activity in a MC38 liver colorectal cancer model by secretion of TNF\u2010\u03b1, IL \u20101\u03b2, and IL \u20106 in the tumor microenvironment. However, in a proinflammatory environment, as observed in a mouse model of autoimmune disease, primary biliary cholangitis, Man impairs the production of TNF\u2010\u03b1, IL\u20101\u03b2, Arg1, and IL\u20106 cytokines. The results probe the dual role of Man in macrophage repolarization in response to the immune system. This study is a proof\u2010of\u2010concept that demonstrates that nanomedicine using specific glycans designed to target other immune cells such as myeloid cells, are a promising strategy not only against cancer but also against other pathologies such as autoimmune diseases.<\/jats:p>","DOI":"10.1002\/advs.202407458","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T06:54:37Z","timestamp":1739516077000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Functional Polarization of Liver Macrophages by Glyco Gold Nanoparticles"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4332-5492","authenticated-orcid":false,"given":"Jennifer","family":"Fernandez Alarcon","sequence":"first","affiliation":[{"name":"Department of Molecular Biochemistry and Pharmacology Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Via Mario Negri 2 Milano 20156 Italy"},{"name":"Grup d'Enginyeria de Materials (GEMAT) Institut Qu\u00edmic de Sarri\u00e0 (IQS) Universitat Ramon Llull (URL)  Via Augusta 390 Barcelona 08017 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4111-216X","authenticated-orcid":false,"given":"Patricia","family":"Perez Schmidt","sequence":"additional","affiliation":[{"name":"Istituto di Scienze e Tecnologie Chimiche \u201cGiulio Natta\u201d  SCITEC\u2010CNR, Via G. 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