Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
Department of Respiratory Diseases, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China.
Front Immunol. 2023 Apr 5;14:1150971. doi: 10.3389/fimmu.2023.1150971. eCollection 2023.
Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are extremely promising nanoscale cell-free therapeutic agents. We previously identified that intravenous administration (IV) of human umbilical cord MSC-EVs (hUCMSC-EVs), especially hypoxic hUCMSC-EVs (Hypo-EVs), could suppress allergic airway inflammation and remodeling. Here, we further investigated the therapeutic effects of Hypo-EVs administration by atomizing inhalation (INH), which is a non-invasive and efficient drug delivery method for lung diseases. We found that nebulized Hypo-EVs produced by the atomization system (medical/household air compressor and nebulizer) maintained excellent structural integrity. Nebulized Dir-labeled Hypo-EVs inhaled by mice were mainly restricted to lungs. INH administration of Hypo-EVs significantly reduced the airway inflammatory infiltration, decreased the levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid (BALF), declined the content of OVA-specific IgE in serum, attenuated the goblet cell metaplasia, and the expressions of subepithelial collagen-1 and α-smooth muscle actin (α-SMA). Notably, Hypo-EV INH administration was generally more potent than Hypo-EV IV in suppressing IL-13 levels and collagen-1 and α-SMA expressions. RNA sequencing revealed that various biological processes, such as cell adhesion, innate immune response, B cell activation, and extracellular space, were associated with the activity of Hypo-EV INH against asthma mice. In addition, Hypo-EVs could load exogenous miR-146a-5p (miR-146a-5p-EVs). Furthermore, INH administration of miR-146a-5p-EVs resulted in a significantly increased expression of miR-146a-5p mostly in lungs, and offered greater protection against the OVA-induced increase in airway inflammation, subepithelial collagen accumulation and myofibroblast compared with nebulized Hypo-EVs. Overall, nebulized Hypo-EVs effectively attenuated allergic airway inflammation and remodeling, potentially creating a non-invasive route for the use of MSC-EVs in asthma treatment.
间充质基质细胞衍生的细胞外囊泡 (MSC-EV) 是极具前途的纳米级无细胞治疗剂。我们之前发现，静脉注射 (IV) 人脐带 MSC-EV (hUCMSC-EV)，特别是低氧 hUCMSC-EV (Hypo-EV)，可以抑制过敏性气道炎症和重塑。在这里，我们通过雾化吸入 (INH) 进一步研究了 Hypo-EV 给药的治疗效果，雾化吸入是一种用于肺部疾病的非侵入性且高效的药物输送方法。我们发现，雾化系统（医用/家用空气压缩机和雾化器）产生的雾化 Hypo-EV 保持了极好的结构完整性。雾化的 DiI 标记 Hypo-EV 被小鼠吸入后主要局限于肺部。INH 给予 Hypo-EV 可显著减少气道炎症浸润，降低支气管肺泡灌洗液 (BALF) 中 IL-4、IL-5 和 IL-13 的水平，降低血清中 OVA 特异性 IgE 的含量，减轻杯状细胞化生，并降低上皮下胶原-1 和 α-平滑肌肌动蛋白 (α-SMA) 的表达。值得注意的是，与 IV 给予 Hypo-EV 相比，INH 给予 Hypo-EV 在抑制 IL-13 水平和胶原-1 和 α-SMA 表达方面通常更有效。RNA 测序表明，各种生物学过程，如细胞黏附、先天免疫反应、B 细胞激活和细胞外空间，与 Hypo-EV INH 抑制哮喘小鼠的活性有关。此外，Hypo-EV 可以负载外源性 miR-146a-5p（miR-146a-5p-EV）。此外，INH 给予 miR-146a-5p-EV 可显著增加 miR-146a-5p 的表达，主要在肺部，与雾化 Hypo-EV 相比，对 OVA 诱导的气道炎症、上皮下胶原积累和肌成纤维细胞增加具有更大的保护作用。总的来说，雾化 Hypo-EV 可有效减轻过敏性气道炎症和重塑，为 MSC-EV 在哮喘治疗中的应用提供了一种非侵入性途径。
