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Here, we investigate how glycosylation (i.e., glucose, galactose, fructose, mannose, and\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetylglucosamine) regulates liposomal nanoparticle interactions with plasma proteins and immune cells, which further determine their biodistribution and therapeutic efficacy. While fructose conferred the greatest enhancement in tumor cell uptake in vitro,\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetylglucosamine\u2010modified nanoparticles achieved the highest tumor accumulation and markedly attenuated systemic clearance in vivo, highlighting a pronounced disparity between in vitro and in vivo performance. The compromised in vivo efficacy of glycosylated nanoparticles was linked to significant clearance in blood, liver, and spleen, primarily mediated by blood monocytes, hepatic stellate cells, and splenic macrophages. Proteomics revealed that adsorption of immunoglobulin G (IgG) and complement C3 facilitates in vivo clearance of nanoparticles. Moreover, IgG deposition further promotes subsequent C3 binding. Notably,\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetylglucosamine markedly mitigates IgG and C3 adsorption, leading to prolonged circulation and enhanced tumor accumulation and inhibition. Benefiting from glycosylation\u2010regulated protein corona, doxorubicin\u2010loaded\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetylglucosamine\u2010modified liposomal nanoparticles achieved superior antitumor efficacy compared with other glycosylated formulations. This study establishes a clear correlation between glycosyl ligand identity, protein corona composition, and in vivo performance, providing fundamental insights for rational design and clinical translation of glycosylated nanomedicines.\n                  <\/jats:p>","DOI":"10.1002\/anie.202520837","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T07:38:34Z","timestamp":1776843514000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Incorporation of Novel Synthetic Glycolipids in Liposomal Nanoparticles Affects Opsonization and In Vivo Clearance"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2060-7390","authenticated-orcid":false,"given":"Yingjie","family":"Yu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Marine Food Processing and Safety Control Key Laboratory of Marine Drugs Chinese Ministry of Education Ocean 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