Reactive oxygen species-responsive dendritic cell-derived exosomes for rheumatoid arthritis

Eun Sook Lee; Jae Hoon Sul; Jung Min Shin; Sol Shin; Jae Ah Lee; Hark Kyun Kim; Yongeun Cho; Hyewon Ko; Soyoung Son; Jeongmi Lee; Sunyoung Park; Dong-Gyu Jo; Jae Hyung Park

doi:10.1016/j.actbio.2021.04.026

Reactive oxygen species-responsive dendritic cell-derived exosomes for rheumatoid arthritis

Acta Biomater. 2021 Jul 1:128:462-473. doi: 10.1016/j.actbio.2021.04.026. Epub 2021 Apr 18.

Authors

Eun Sook Lee¹, Jae Hoon Sul², Jung Min Shin³, Sol Shin⁴, Jae Ah Lee¹, Hark Kyun Kim², Yongeun Cho², Hyewon Ko⁵, Soyoung Son⁶, Jeongmi Lee², Sunyoung Park², Dong-Gyu Jo⁷, Jae Hyung Park⁸

Affiliations

¹ School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
² School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
³ School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Department of Genetic Resources Research, National Marine Biodiversity Institute of Korea (MABIK), Seocheon, Chungnam, 33662, Republic of Korea.
⁴ Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
⁵ School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
⁶ School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
⁷ School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address: jodg@skku.edu.
⁸ School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address: jhpark1@skku.edu.

PMID: 33878476
DOI: 10.1016/j.actbio.2021.04.026

Abstract

Although tolerogenic dendritic cell-derived exosomes (TolDex) have emerged as promising therapeutics for rheumatoid arthritis (RA), their clinical applications have been hampered by their poor in vivo disposition after systemic administration. Herein, we report the development of stimuli-responsive TolDex that induces lesion-specific immunoregulation in RA. Responsiveness to reactive oxygen species (ROS), a physiological stimulus in the RA microenvironment, was conferred on TolDex by introducing a thioketal (TK) linker-embedded poly(ethylene glycol) (PEG) on TolDex surface via hydrophobic insertion. The detachment of PEG following overproduction of ROS facilitates the cellular uptake of ROS-responsive TolDex (TKDex) into activated immune cells. Notably, TolDex and TKDex downregulated CD40 in mature dendritic cells (mDCs) and regulated secretion of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) at the cellular level. In the collagen-induced arthritis (CIA) mouse model, PEG prolonged the blood circulation of TKDex following intravenous administration and enhanced their accumulation in the joints. In addition, TKDex decreased IL-6, increased transforming growth factor-β, and induced the CD4⁺CD25⁺Foxp3⁺ regulatory T cells in CIA mice. Overall, ROS-responsive TolDex might have potential as therapeutic agents for RA. STATEMENT OF SIGNIFICANCE: Tolerogenic dendritic cell-derived exosomes (TolDex) are emerging immunoregulators of autoimmune diseases, including rheumatoid arthritis (RA). However, their lack of long-term stability and low targetability are still challenging. To overcome these issues, we developed reactive oxygen species (ROS)-responsive TolDex (TKDex) by incorporating the ROS-sensitive functional group-embedded poly(ethylene glycol) linker into the exosomal membrane of TolDex. Surface-engineered TKDex were internalized in mature DCs because of high ROS-sensitivity and enhanced accumulation in the inflamed joint in vivo. Further, for the first time, we investigated the potential mechanism of action of TolDex relevant to CD40 downregulation and attenuation of tumor necrosis factor (TNF)-α secretion. Our strategy highlighted the promising nanotherapeutic effects of stimuli-sensitive TolDex, which induces immunoregulation.

Keywords: Exosome; Immunoregulation; ROS-responsive; Rheumatoid arthritis; Surface modification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arthritis, Experimental* / drug therapy
Arthritis, Rheumatoid* / drug therapy
Cytokines
Dendritic Cells
Exosomes*
Mice
Reactive Oxygen Species

Substances

Cytokines
Reactive Oxygen Species