An Jiwon, Choi Moonhwan, Kim Sol, Yoon Hyungkyung, Jang An-Soo, Lee Sang-Kyung, Rhim Taiyoun
Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04763, Korea.
Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, Korea.
Biomater Res. 2025 Jan 31;29:0136. doi: 10.34133/bmr.0136. eCollection 2025.
This study introduces a novel gene delivery system, polyethyleneimine modified with isoprenaline (PEI-isoprenaline), to enhance targeted gene delivery in the context of asthma therapy and airway remodeling. In vitro investigations used Beas2B cells to assess the biocompatibility of isoprenaline, PEI-isoprenaline, and small interfering RNA (siRNA)/PEI-isoprenaline complexes, with cytotoxicity evaluations confirming their safety. The transfection efficiency of the siRNA/PEI-isoprenaline complex was scrutinized in THP-1 cells and displayed superior performance in delivering siRNA to cells expressing the β2 adrenergic receptor (ADRB2). In vivo studies used a murine chronic asthma model to evaluate gene delivery to ADRB2-expressing cells in bronchoalveolar fluid and lung tissues. Therapeutic effects were comprehensively assessed through cell analyses, revealing substantial reductions in airway inflammatory cells and fibrosis, particularly in the Arg1 siRNA/PEI-isoprenaline group. The siRNA/PEI-isoprenaline complex exhibited an impressive 80% delivery rate, greatly surpassing the performance of polyethyleneimine 2K (20%). Notably, the complex achieved a substantial 63% reduction in arginase-1 gene expression, validating its therapeutic potential. Noteworthy inhibitory effects on airway hyperresponsiveness were observed, underscoring the complex's potential as a targeted gene delivery system for asthma treatment. Our findings underscore the promise and effectiveness of the PEI-isoprenaline complex as a gene delivery system, with its demonstrated biocompatibility, transfection efficiency, and therapeutic outcomes, including arginase-1 gene knockdown and mitigation of airway inflammation and fibrosis, indicating it as a promising candidate for advancing asthma therapy and contributing to the understanding and control of airway remodeling in respiratory diseases.
本研究引入了一种新型基因递送系统，即经异丙肾上腺素修饰的聚乙烯亚胺（PEI-异丙肾上腺素），以在哮喘治疗和气道重塑的背景下增强靶向基因递送。体外研究使用Beas2B细胞评估异丙肾上腺素、PEI-异丙肾上腺素和小干扰RNA（siRNA）/PEI-异丙肾上腺素复合物的生物相容性，细胞毒性评估证实了它们的安全性。在THP-1细胞中对siRNA/PEI-异丙肾上腺素复合物的转染效率进行了仔细研究，结果显示其在将siRNA递送至表达β2肾上腺素能受体（ADRB2）的细胞方面表现优异。体内研究使用小鼠慢性哮喘模型评估向支气管肺泡灌洗液和肺组织中表达ADRB2的细胞的基因递送情况。通过细胞分析全面评估了治疗效果，结果显示气道炎症细胞和纤维化显著减少，尤其是在Arg1 siRNA/PEI-异丙肾上腺素组。siRNA/PEI-异丙肾上腺素复合物的递送率高达80%，大大超过了2K聚乙烯亚胺（20%）的性能。值得注意的是，该复合物使精氨酸酶-1基因表达大幅降低了63%，证实了其治疗潜力。观察到对气道高反应性有显著的抑制作用，突出了该复合物作为哮喘治疗靶向基因递送系统的潜力。我们的研究结果强调了PEI-异丙肾上腺素复合物作为基因递送系统的前景和有效性，其已证明的生物相容性、转染效率和治疗效果，包括精氨酸酶-1基因敲低以及减轻气道炎症和纤维化，表明它是推进哮喘治疗以及促进对呼吸系统疾病气道重塑的理解和控制的有前途的候选物。
