Reversing Macrophage Immunometabolic Dysfunction in Prolonged Infections Via a Glutaminolysis-Fueled Restoration-Based Hierarchically Selective Therapeutic System.

Prolonged implant-associated bone infection (IBI) fosters an immunosuppressive niche by disrupting the essential immunometabolic reprogramming required for macrophages to support antibacterial immune responses. Mechanistically, our work demonstrates that prolonged infection substantially impairs macrophage immune function by triggering a profound downregulation of glutaminase 1 (GLS1) to stifle glutaminolysis-fueled anaplerosis. Glutaminolysis-fueled dysfunction weakens glutamine-derived mitochondrial reactive oxygen species (mtROS) bursts in macrophages, leading to severe deterioration of IBIs. Herein, we present a hierarchically selective therapeutic system (mGls@HEV-MTP) for glutaminolysis-fueled restoration in macrophages via hierarchical infection-to-macrophage selective GLS1 mRNA delivery. The mGls@HEV-MTP, surface-integrated with mannose-functionalized antibacterial peptide (MTP) via an acid-cleavable hydrazone bond, exploits its acid-responsive property to decorate bacterial surfaces with mannose residues and ensure acid-triggered prerelease of mGls@HEV for selective macrophage uptake in the acidic infection niche. This nano-immunotherapeutic platform orchestrates bactericidal macrophage repolarization by restoring GLS1-driven glutaminolysis-fueled anaplerosis and simultaneously marking invading pathogens with an immune-recognition signal, addressing both immunosuppression and poor immunogenicity in the infection niche. Notably, this work reveals the importance of glutaminolysis-fueled anaplerosis in sustaining macrophage antibacterial immunity and provides a promising immunotherapeutic strategy for IBI eradication.