Isoprenaline-Modified Polyethyleneimine as an Efficient Gene Delivery System for Targeted Asthma Therapy and Airway Remodeling Inhibition

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.