Small Extracellular Vesicles Derived From MSCs Have Immunomodulatory Effects to Enhance Delivery of ASO-210 for Psoriasis Treatment

Abstract

Mesenchymal stem cells (MSCs) have been increasingly used for treating autoimmune diseases due to their immune modulation functions, but inefficient homing to the target tissue and safety issues limits their wide application. Recently, increasing studies demonstrate small extracellular vesicles (sEVs) as key mediators of MSCs to exert their immunomodulatory effects. In this study, we found that sEVs derived from human umbilical cord MSCs stimulated by IFN-γ (IFNγ-sEVs) inhibited proliferation and activation of peripheral blood mononuclear cells and T cells in vitro. Furthermore, we confirmed that IFNγ-sEVs reduced psoriasis symptoms including thickness, erythema, and scales of skin lesions; exhausted Th17 cells, increased Th2 cells; and reduced enrichment of inflammatory cytokines such as IL-17A, IFN-γ, IL-6, and TNF-α in both spleen and skin lesions in vivo. Importantly, IFNγ-sEVs significantly improved the delivery efficiency and stability of ASO-210, the antisense oligonucleotides of miR-210 block the immune imbalance and subsequent psoriasis development. Our results reveal MSC-sEVs as promising cell-free therapeutic agents and ideal delivery vehicles of antisense oligonucleotides for psoriasis treatment.

Circ_0011129 Encapsulated by the Small Extracellular Vesicles Derived from Human Stem Cells Ameliorate Skin Photoaging

“…The results showed that the CM cultured in the 3D bioreactor (3D-R-CM) achieved the best anti-photoaging effect comparing with 2D and 3D spheroids culture (3D-S-CM) ( Figure 1 H,I). Previously, we and others have reported that MSCs secret small extracellular vesicles (MSC-sEVs) as cell-free vectors in alternative therapies for a variety of inflammatory diseases due to their potential to regulate inflammatory immune responses [ 27 ]. To test if the sEVs in the culture medium play a major role in anti-photoaging function, we isolated sEVs in 3D-R-CM by differential centrifugation, and found that sEVs is the major player of 3D-R-CM involved in anti-photoaging process ( Figure 1 J,K).…”

Mesenchymal Stem Cells and Psoriasis: Systematic Review

“…In addition, the stem cell secretome can be manipulated and made more suitable for therapeutic purposes for psoriasis. Indeed, the same research group demonstrated the efficacy of administering small extracellular vesicles derived from huc-MSCs transduced with a mirna with anti-inflammatory properties (miR-210) in mouse models of psoriasis [ 49 ].…”

“…The researchers claim that the small extracellular vesicles (EVs) produced by MSCs could potentially be more effective and have fewer side effects than whole-cell therapy. Research in this area could evolve toward producing new mesenchymal stem cell secretome-based topical therapies that could potentially be effective [ 48 , 49 ].…”

Recent advances in exosome-mediated nucleic acid delivery for cancer therapy

“…As a common strategy, electroporation also allows DNA to be loaded into exosomes through creating pores on exosomal lipid bilayers. It has been shown that ASO4, ASO-210 or scramble ASO loaded into exosomes by electroporation could be delivered to recipient cells and knock down specific gene expression [ 59 – 61 ]. However, a major disadvantage of electroporation is the formation of nucleic acid and exosome aggregates during encapsulation, which will affect the function of nucleic acids [ 62 ].…”