Shield and sword nano-soldiers ameliorate rheumatoid arthritis by multi-stage manipulation of neutrophils.

Rheumatoid arthritis (RA) is characterized by the outbreak of inflammation. Neutrophils, the main culprit of the outbreak of inflammation, are the first inflammatory cells to be recruited to inflamed joints and facilitate the recruitment of themselves by stimulating the release of chemokines. Here, based on neutrophils, a novel anti-inflammatory "shield and sword soldiers" strategy is established with LMWH-TOS nanoparticles (LT NPs). The hydrophilic fragment low molecular weight heparin (LMWH) acts as a shield which block the transvascular movement of neutrophils through inhibiting the adhesion cascade by binding to P-selectin on inflamed endothelium. Synergistically, MMP-9, which is secreted by the recruited neutrophils and degrade the main component of articular cartilage, is reduced by the hydrophobic fragment d-α-tocopheryl succinate (TOS), functioning as a sword. In collagen-induced arthritis (CIA) mouse model, LT NPs show significant targeting effect, and exhibit prominent therapeutic efficacy after enveloping the first-line anti-RA drug methotrexate. Our work proves that the multi-stage manipulation of neutrophils is feasible and effective, providing a new concept for RA treatment. [Display omitted] • Nanoparticles for RA treatment were assembled from LMWH and TOS, which can regulate neutrophils in multiple stages. • By binding to P-selectin, LMWH can target the inflamed endothelium in inflamed joints. • LMWH can interrupt the recruitment of neutrophils by competitively inhibiting the combination of P-selectin and PSGL-1. • TOS can suppress the secretion of MMP-9 of neutrophils, thereby leaving neutrophils hamstrung in its cartilage destruction. [ABSTRACT FROM AUTHOR]