Single‐Chain Anti‐IL‐1β Antibody Carried by Outer Membrane Vesicles of Bacteroides fragilis Alleviates Tubular Inflammation in Chronic Kidney Disease

ABSTRACT Microinflammation is a key driver of chronic kidney disease (CKD) progression, with interleukin‐1β (IL‐1β) playing a pivotal role. However, current anti‐IL‐1β antibody therapies face critical limitations, such as systemic side effects and substantial production costs, which hinder their therapeutic efficacy and clinical translation for CKD intervention. To address this, we developed Bacteroides fragilis ‐derived outer membrane vesicles (OMVs) encapsulating anti‐IL‐1β single‐chain variable fragment (scFv) and conjugated with kidney‐targeting peptides (KKEEE) 3 K. Engineered OMV‐(KKEEE) 3 K‐scFv's safety was evaluated in vitro (24, 48 h) and in vivo (2 months). Its anti‐inflammatory efficacy was assessed in a high glucose‐induced model in vitro, and in various kidney disease mouse models (streptozotocin‐induced diabetic nephropathy, lupus nephritis, unilateral ureteral obstruction) in vivo. OMV‐(KKEEE) 3 K‐scFv showed high stability, precisely delivered scFv to proximal renal tubules, had excellent safety, reduced the expression of inflammatory cytokines including tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6) and monocyte chemoattractant protein‐1 (MCP‐1), decreased cell infiltration, and alleviated renal injury. In conclusion, engineered OMVs effectively deliver anti‐IL‐1β scFv, mitigating local inflammation and CKD‐related renal damage.