Elimination of airway inflammatory cells is essential for asthma control. As Bcl-2 protein is highly expressed on the mitochondrial outer membrane in inflammatory cells, we chose a Bcl-2 inhibitor, ABT-199, which can inhibit airway inflammation and airway hyperresponsiveness by inducing inflammatory cell apoptosis. Herein, we synthesized a pH-sensitive nanoformulated Bcl-2 inhibitor (Nf-ABT-199) that could specifically deliver ABT-199 to the mitochondria of bronchial inflammatory cells. The proof-of-concept study of an inflammatory cell mitochondria-targeted therapy using Nf-ABT-199 was validated in a mouse model of allergic asthma. Nf-ABT-199 was proven to significantly alleviate airway inflammation by effectively inducing eosinophil apoptosis and inhibiting both inflammatory cell infiltration and mucus hypersecretion. In addition, the nanocarrier or Nf-ABT-199 showed no obvious influence on cell viability, airway epithelial barrier and liver function, implying excellent biocompatibility and with non-toxic effect. The nanoformulated Bcl-2 inhibitor Nf-ABT-199 accumulates in the mitochondria of inflammatory cells and efficiently alleviates allergic asthma.

消除气道炎性细胞对于控制哮喘至关重要。由于Bcl-2蛋白在炎症细胞的线粒体外膜上高表达，因此我们选择了Bcl-2抑制剂ABT-199，它可以通过诱导炎症细胞凋亡来抑制气道炎症和气道高反应性。在这里，我们合成了一种pH敏感的纳米Bcl-2抑制剂（Nf-ABT-199），该抑制剂可以将ABT-199特异性地递送至支气管炎性细胞的线粒体。在过敏性哮喘的小鼠模型中验证了使用Nf-ABT-199靶向炎症细胞线粒体疗法的概念验证研究。Nf-ABT-199被证明可通过有效诱导嗜酸性粒细胞凋亡并抑制炎性细胞浸润和粘液分泌过多而显着减轻气道炎症。此外，纳米载体或Nf-ABT-199对细胞活力，气道上皮屏障和肝功能无明显影响，表明其良好的生物相容性且无毒。纳米级Bcl-2抑制剂Nf-ABT-199积聚在炎症细胞的线粒体中，可有效缓解过敏性哮喘。