An injectable hydrogel to disrupt neutrophil extracellular traps for treating rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA), an autoimmune disease, is characterized by inflammatory cell infiltration that damages cartilage, disrupts bone, and impairs joint function. The therapeutic efficacy of RA treatments with the severely affected side remains unsatisfactory despite current treatment methods that primarily focus on anti-inflammatory activity, largely because of the complicatedly pathological mechanisms. A recently identified mechanism for RA development involves the interaction of RA autoantibodies with various proinflammatory cytokines to facilitate the formation of neutrophil extracellular traps (NETs), which increased inflammatory responses to express inflammatory cytokines and chemokines. Therefore, NETs architecture digestion may inhibit the positive-feedback inflammatory signal pathway and lessen joint damage in RA. In this work, deoxyribonuclease I (DNase) is connected to oxidized hyaluronic acid (OHA) via Schiff base reaction to extend the half-life of DNase. The modification does not influence the DNase activity for plasmid deoxyribonucleic acid hydrolysis and NETs’ architecture disruption. Carboxymethyl chitosan is crosslinked with DNase-functionalised OHA (DHA) to form an injectable, degradable, and biocompatible hydrogel (DHY) to further strengthen the adhesive capability of DHA. Importantly, the collagen-induced arthritis model demonstrates that intra-articular injection of DHY can significantly reduce inflammatory cytokine expression and alleviate RA symptoms, which can be significantly improved by combining methotrexate. Here, a DNase-functionalised hydrogel has been developed for RA treatment by constantly degrading the novel drug target of NETs to decrease inflammatory response in RA.

Keywords:

• Rheumatoid arthritis
• deoxyribonuclease
• neutrophil extracellular traps
• anti-inflammation
• hydrogel

Acknowledgements

The picture of the knee joint in Scheme 1 was modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License.

Disclosure statement

The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors without undue reservation.

Ethics statement

This animal study was reviewed and approved by the Animal Ethics Committee of the First Hospital of Jilin University (NO. 20220026).

Author contributions

C. Zhao conceived the idea and designed the experiments. N. Wang and J. Ma performed the experiments and analyzed the data. W. Song helped analyze the data and provided valuable advice. N. Wang and C. Zhao co-wrote the manuscript. All authors have discussed the results of this study.

Additional information

Funding

This work was supported by the Scientific and Technological Development programme of Jilin Province (No. 20210101358JC).