Synovial fibroblast-targeting liposomes encapsulating an NF-κB-blocking peptide ameliorates zymosan-induced synovial inflammation.

Changcheng You,Xiaoqi Liu,Jinglong Yan,Rongzhi Wei,Jianing Zu,Chengchao Song,Yufu Wang,Changlong Zhou,Pengyu Kong

doi:10.1111/jcmm.13549

Changcheng You, Xiaoqi Liu + Show 7 more

Open Access

https://doi.org/10.1111/jcmm.13549

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Abstract

Synovial fibroblasts (SFs) play a crucial role in the inflammatory process of rheumatoid arthritis (RA). The highly activated NF‐κB signal in SFs is responsible for most of the synovial inflammation associated with this disease. In this study, we have developed an SF‐targeting liposomal system that encapsulates the NF‐κB‐blocking peptide (NBD peptide) HAP‐lipo/NBD. HAP‐lipo/NBDs demonstrated efficient SF‐specific targeting in vitro and in vivo. Our study also showed a significant inhibitory effect of HAP‐lipo/NBD on NF‐κB activation, inflammatory cytokine release and SF migration capability after zymosan stimulation. Furthermore, the systemic administration of HAP‐lipo/NBDs significantly inhibited synovial inflammation and improved the pathological scores of arthritis induced by zymosan. Thus, these results suggest that an SF‐targeting NF‐κB‐blocking strategy is a potential approach for the development of alternative, targeted anti‐RA therapies.

Highlights

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by inflammation in the synovium and the destruction of cartilage and bone.[1]
Synovial fibroblasts in the synovial lining play a crucial role in producing both cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction.[21,22]
We demonstrated that the inhibitory effect of HAP-lipo/NEMO-binding domain (NBD) on synovial inflammation is through the targeted suppression of NF-jB activation in synovial fibroblasts (SFs)

Summary

| INTRODUCTION

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by inflammation in the synovium and the destruction of cartilage and bone.[1]. The behaviour of SFs is regulated by multiple intracellular pathways and involves interferon regulatory factors, activator protein-1, mitogen-activated protein kinase and the nuclear factor-kappa B (NF-jB).[2,5] The highly activated NF-jB signal in RA is responsible for the pathological process of RA.[6] NF-jB regulates proinflammatory genes such as TNF-a, IL-6 and IL-8 and the transcription of adhesion molecule-1 and matrix-degrading enzymes (MMP-3, MMP-9, etc.).[7,8] NF-jB provides a key survival signal that suppresses apoptosis in SFs.[2] Therapeutic agents targeting NF-jB have exhibited various degrees of effectiveness in arthritis Few of these compounds are SF-specific, and some deleterious effects have been reported.[9] the development of compounds that target SFs may complement current therapies and avoid major side effects.[10] Nanoparticles hold significant. We describe an SF-specific liposome with inhibitory activity against NF-jB and evaluate the therapeutic potential of this nanoparticle in the treatment of inflammatory arthritis

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION