Engineered Cytokine‐Primed Extracellular Vesicles with High PD‐L1 Expression Ameliorate Type 1 Diabetes

Abstract

Type 1 diabetes (T1D), which is a chronic autoimmune disease, results from the destruction of insulin‐producing β cells targeted by autoreactive T cells. The recent discovery that mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) function as therapeutic tools for autoimmune conditions has attracted substantial attention. However, the in vivo distribution and therapeutic effects of MSC‐EVs potentiated by pro‐inflammatory cytokines in the context of T1D have yet to be established. Here, it is reported that hexyl 5‐aminolevulinate hydrochloride (HAL)‐loaded engineered cytokine‐primed MSC‐EVs (H@TI‐EVs) with high expression of immune checkpoint molecule programmed death‐legend 1 (PD‐L1) exert excellent inflammatory targeting and immunosuppressive effects for T1D imaging and therapy. The accumulated H@TI‐EVs in injured pancreas not only enabled the fluorescence imaging and tracking of TI‐EVs through the intermediate product protoporphyrin (PpIX) generated by HAL, but also promoted the proliferative and anti‐apoptotic effects of islet β cells. Further analysis revealed that H@TI‐EVs exhibited an impressive ability to reduce CD4+ T cell density and activation through the PD‐L1/PD‐1 axis, and induced M1‐to‐M2 macrophage transition to reshape the immune microenvironment, exhibiting high therapeutic efficiency in mice with T1D. This work identifies a novel strategy for the imaging and treatment of T1D with great potential for clinical application.

Recent advances in extracellular vesicle engineering and its applications to regenerative medicine

“…Additionally, using these characteristics, TI-primed UCMSC EV with increased PD-L1 expression can suppress CD4+ T cells, preventing cell destruction of β cells and demonstrating therapeutic effects in Type 1 diabetes (T1D), an autoimmune disease (Fig. 6 B) [ 71 ]. The M1/M2 polarization effect can also be facilitated by EVs derived from GMSCs treated with TNF-α (50 ng/ml) and IFN-α (50 ng/ml), due to an increase in the expression levels of CD73 and CD5L [ 72 ].…”

“…B High expression of PD-L1 and applications for immunotherapy in type 1 diabetes with TNF-α and INF-γ preconditioned MSC derived EV (TI-EV). Reproduced with permission from [ 71 ]. Copyright 2023 John Wiley & Sons …”

The MSC-EV-microRNAome: A Perspective on Therapeutic Mechanisms of Action in Sepsis and ARDS

“…Several licensing strategies reliably enhance MSC-derived EV immunoregulatory and therapeutic effects. These priming strategies include pre-exposure to TNFα, IL-1β, IFN-γ alone or in combination [28,75,76,105,[108][109][110][111][112][113][114][115][116][117]; TLR ligands such as LPS [118][119][120], hypoxia [121,122], or other factors, including thrombin [107], the endoplasmic reticulum stress inducer, thapsigargin [123], and the lipophilic photosensitizer, hexyl-5-aminolevulinate hydrochloride (HAL) in combination with pro-inflammatory cytokines [113]; transfection with miR [124]; or serum from injury models [20,34,43], BALF, as above; or secretome from LPS-activated cells such as microglia [125]. EVs derived from licensed or primed MSCs have been investigated in an array of inflammatory conditions and while the pathogenic factors driving specific diseases may differ, there is a large consensus across studies demonstrating the protective and immunoregulatory effects of MSC-derived EVs.…”

“…EVs derived from licensed or primed MSCs have been investigated in an array of inflammatory conditions and while the pathogenic factors driving specific diseases may differ, there is a large consensus across studies demonstrating the protective and immunoregulatory effects of MSC-derived EVs. Much attention has been centered on the relevance of priming strategies on macrophage polarization [43,75,76,105,109,113,116,[119][120][121][122][123]125] or transition toward pro-resolution of infection or inflammatory cellular phenotypes [112,118].…”

Therapeutic Efficacy of Interferon-Gamma and Hypoxia-Primed Mesenchymal Stromal Cells and Their Extracellular Vesicles: Underlying Mechanisms and Potentials in Clinical Translation

“…Other than that, numerous studies have harnessed the immunomodulatory property of MSCs for treating Type I diabetes, which is a well-known autoimmune disease characterized by specific adaptive immunity against β-cell antigens [ 50 , 68 , 69 ]. For instance, Wang et al demonstrated that cytokine-primed MSC-EVs exhibited high levels of the immune checkpoint molecule PD-L1, which significantly reduced CD4 + T cell density and activation via the PD-L1/PD-1 axis and promoted the transition of macrophages from the M1 to M2 phenotype in mice with Type I diabetes [ 69 ]. Pancreatic islet transplantation is a therapeutic option for treating Type I diabetes; however, acute islet loss is a significant complication of this procedure.…”