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

Abstract

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.