Neutrophil-hitchhiking nanodrug precisely silences neutrophil activation and rebuilds immune homeostasis in rheumatoid arthritis without compromising host defense.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease, and current antirheumatic drugs have poor efficacy or cause considerable systemic adverse reactions. Neutrophil activation is a central driver of RA pathogenesis; however, approaches that curb pathogenic neutrophil activity while preserving host defense are lacking. In patients with RA, we identified spleen tyrosine kinase (SYK) as a key upstream regulator whose aberrant activation drives neutrophil hyperactivation, neutrophil extracellular trap (NET) formation, inflammatory mediator release, and delayed apoptosis, while preserving antimicrobial function. Moreover, we engineered a HSA-AAPV-TKI (HAT) nanodrug by conjugating human serum albumin (HSA) to a SYK-targeted tyrosine kinase inhibitor (TKI) via a neutrophil elastase-cleavable AAPV peptide linker (Ala-Ala-Pro-Val). HAT is preferentially internalized by circulating neutrophils in CIA mice, traffics with them to inflamed joints, and releases the inhibitor in response to local neutrophil activation, thereby attenuating SYK signaling and pathogenic neutrophil functions while largely preserving antimicrobial activity. In a collagen-induced arthritis mouse model, HAT significantly reduced joint swelling, arthritis scores, and structural joint damage without impairing host defense. This strategy establishes a new RA therapeutic avenue that reconciles potent efficacy with immune safety and represents a milestone toward translational neutrophil-targeted therapy.