Pulmonary fibrosis is a serious respiratory disease, with limited therapeutic options. Since TGF-β is a critical factor in the fibrotic process, downregulation of this cytokine has been considered a potential approach for disease treatment. Herein, we designed a new lung-targeted delivery technology based on the complexation of polymeric antisense oligonucleotides (pASO) and dimeric human β-defensin 23 (DhBD23). Antisense oligonucleotides targeting TGF-β mRNA were polymerized by rolling circle amplification and complexed with DhBD23. After complexation with DhBD23, pASO showed improved serum stability and enhanced uptake by fibroblasts in vitro and lung-specific accumulation upon intravenous injection in vivo. The pASO/DhBD23 complex delivered into the lung downregulated target mRNA, and subsequently alleviated lung fibrosis in mice, as demonstrated by western blotting, quantitative reverse-transcriptase PCR (qRT-PCR), immunohistochemistry, and immunofluorescence imaging. Moreover, as the complex was prepared only with highly biocompatible materials such as DNA and human-derived peptides, no systemic toxicity was observed in major organs. Therefore, the pASO/DhBD23 complex is a promising gene therapy platform with lung-targeting ability to treat various pulmonary diseases, including pulmonary fibrosis, with low side effects.

中文翻译：

---

TGF-β反义寡核苷酸的肺靶向治疗可治疗肺纤维化。

肺纤维化是一种严重的呼吸系统疾病，治疗选择有限。由于TGF-β是纤维化过程中的关键因素，因此该细胞因子的下调被认为是治疗疾病的潜在方法。本文中，我们基于聚合反义寡核苷酸（pASO）和二聚体人β-防御素23（DhBD23）的复合物，设计了一种新型的肺靶向递送技术。通过滚环扩增使靶向TGF-βmRNA的反义寡核苷酸聚合并与DhBD23复合。与DhBD23络合后，pASO在体外显示出改善的血清稳定性并被成纤维细胞吸收，而在体内静脉内注射后显示出肺特异性积累。pASO / DhBD23复合物被递送到肺中，从而下调了靶mRNA的含量，随后减轻了小鼠的肺纤维化，如Western blotting，定量逆转录酶PCR（qRT-PCR），免疫组织化学和免疫荧光成像所证实。此外，由于该复合物仅用高度生物相容的材料（例如DNA和人源肽）制备，因此在主要器官中未观察到全身毒性。因此，pASO / DhBD23复合物是一种有前途的基因治疗平台，具有靶向肺的能力，可以治疗各种肺部疾病，包括肺纤维化，且副作用低。