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Mechanistically, our work demonstrates that prolonged infection substantially impairs macrophage immune function by triggering a profound downregulation of glutaminase 1 (GLS1) to stifle glutaminolysis\u2010fueled anaplerosis. Glutaminolysis\u2010fueled dysfunction weakens glutamine\u2010derived mitochondrial reactive oxygen species (mtROS) bursts in macrophages, leading to severe deterioration of IBIs. Herein, we present a hierarchically selective therapeutic system (mGls@HEV\u2010MTP) for glutaminolysis\u2010fueled restoration in macrophages via hierarchical infection\u2010to\u2010macrophage selective GLS1 mRNA delivery. The mGls@HEV\u2010MTP, surface\u2010integrated with mannose\u2010functionalized antibacterial peptide (MTP) via an acid\u2010cleavable hydrazone bond, exploits its acid\u2010responsive property to decorate bacterial surfaces with mannose residues and ensure acid\u2010triggered prerelease of mGls@HEV for selective macrophage uptake in the acidic infection niche. This nano\u2010immunotherapeutic platform orchestrates bactericidal macrophage repolarization by restoring GLS1\u2010driven glutaminolysis\u2010fueled anaplerosis and simultaneously marking invading pathogens with an immune\u2010recognition signal, addressing both immunosuppression and poor immunogenicity in the infection niche. Notably, this work reveals the importance of glutaminolysis\u2010fueled anaplerosis in sustaining macrophage antibacterial immunity and provides a promising immunotherapeutic strategy for IBI eradication.<\/jats:p>","DOI":"10.1002\/advs.77500","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:37:01Z","timestamp":1789101421000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reversing Macrophage Immunometabolic Dysfunction in Prolonged Infections Via a Glutaminolysis\u2010Fueled Restoration\u2010Based Hierarchically Selective Therapeutic System"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9913-7813","authenticated-orcid":false,"given":"Weinan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou City Zhejiang Province People's Republic of 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