Targeting the PGRN‐BMP Lysosomal Axis With NPs@PGRN Reverses Immunometabolic Dysfunction in Chronic Septic Arthritis

ABSTRACT Chronic septic arthritis, often progressing to refractory infection due to intracellular bacterial persistence, is accompanied by dynamic macrophage immunometabolic reprogramming. Prolonged intracellular bacterial survival drives lipid metabolic remodeling in macrophages, leading to progressive accumulation of bis(monoacylglycero)phosphate (BMP), regulated by progranulin (PGRN). Mechanistically, PGRN maintains lysosomal homeostasis through direct interaction with BMP. PGRN deficiency disrupts lysosomal integrity, induces immunosuppressive polarization, and facilitates bacterial immune evasion. To address this, a dual‐targeting nanoparticle system (NPs@PGRN) targeting the “PGRN‐BMP‐lysosome” axis was developed. NPs@PGRN restores lysosomal bactericidal capacity via PGRN replenishment, significantly reduces bacterial burdens, and reprograms macrophage immunophenotypes toward antimicrobial competence. This study elucidates the central role of lipid‐immune crosstalk in chronic joint infection pathogenesis and provides a novel therapeutic strategy for it.