Dong Shengting, Fang Huapan, Zhu Junjie, Wu Zhiqiang, Liu Yi, Zhu Jiafei, Ma Benting, Chen Qian, Yang Yang
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.
Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China.
ACS Nano. 2025 Jan 21;19(2):2742-2758. doi: 10.1021/acsnano.4c15130. Epub 2025 Jan 10.
For idiopathic pulmonary fibrosis (IPF), interleukin 11 (IL-11) is a pivotal cytokine that stimulates the transformation of fibroblasts into myofibroblasts, thus accelerating the progression of pulmonary fibrosis. Here, we develop an innovative inhalable small interfering RNA (siRNA) delivery system termed PEI-GBZA, which demonstrates impressive efficiency in loading siIL-11 targeting IL-11 (siIL-11) and substantially suppresses the differentiation of fibroblasts into myofibroblasts and epithelial-mesenchymal transition (EMT), reduces neutrophil and macrophage recruitment, and ultimately relieves the established fibrotic lesions in the IPF model. PEI-GBZA is prepared by modifying low-molecular-weight polyethylenimine (PEI) with 4-guanidinobenzoic acid (GBZA). The resulting PEI-GBZA may effectively encapsulate siIL-11 through a variety of interactions such as hydrophobic, hydrogen bonding, and electrostatic interactions, creating stable carrier/siIL-11 nanoparticles (PEI-GBZA/siIL-11 NPs). Upon inhalation, PEI-GBZA/siIL-11 NPs demonstrate effective retention in fibrotic lesions, leading to a marked mitigation of disease progression in a bleomycin-induced pulmonary fibrosis model. Impressively, this inhalation therapy exhibits negligible systemic toxicity. This work provides a universal and noninvasive RNA therapeutic delivery platform that holds significant promise for respiratory diseases. The potential for clinical application of this platform is substantial, offering a frontier for the treatment of IPF and potentially other pulmonary disorders.
对于特发性肺纤维化（IPF），白细胞介素11（IL-11）是一种关键细胞因子，可刺激成纤维细胞向肌成纤维细胞转化，从而加速肺纤维化进程。在此，我们开发了一种创新的可吸入小干扰RNA（siRNA）递送系统，称为PEI-GBZA，它在装载靶向IL-11的siIL-11方面表现出令人印象深刻的效率，并能显著抑制成纤维细胞向肌成纤维细胞的分化以及上皮-间质转化（EMT），减少中性粒细胞和巨噬细胞的募集，最终缓解IPF模型中已形成的纤维化病变。PEI-GBZA是通过用4-胍基苯甲酸（GBZA）修饰低分子量聚乙烯亚胺（PEI）制备而成。所得的PEI-GBZA可通过疏水、氢键和静电相互作用等多种相互作用有效地包封siIL-11，形成稳定的载体/siIL-11纳米颗粒（PEI-GBZA/siIL-11 NPs）。吸入后，PEI-GBZA/siIL-11 NPs在纤维化病变中表现出有效的滞留，从而在博来霉素诱导的肺纤维化模型中显著减轻疾病进展。令人印象深刻的是，这种吸入疗法表现出可忽略不计的全身毒性。这项工作提供了一个通用的、非侵入性的RNA治疗递送平台，对呼吸系统疾病具有重大前景。该平台的临床应用潜力巨大，为IPF及其他潜在肺部疾病的治疗开辟了一个前沿领域。
