Wang Yangeng, Xuan Wenzhe, Mao Chengqiong, Liu Yang
School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, PR China.
Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 510180, PR China.
Acta Biomater. 2025 Jul 31. doi: 10.1016/j.actbio.2025.07.068.
Inhalable nucleic acid drug delivery systems have garnered increasing attention as a promising strategy for the treatment of chronic pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF). These diseases are often characterized by chronic inflammation, airway remodeling, and progressive lung dysfunction, posing significant clinical challenges. Nucleic acid therapeutics, including plasmid DNA, messenger RNA (mRNA), microRNA (miRNA), small interfering RNAs (siRNAs), and antisense oligonucleotides (ASOs), offer the potential to correct genetic defects, modulate aberrant gene expression, or suppress pathogenic signaling pathways. The inhalation route enables direct, non-invasive access to the lungs, offering localized delivery, rapid onset of action, and reduced systemic side effects. However, the lung presents multiple biological barriers that limit the delivery and activity of nucleic acids, including mucus clearance, enzymatic degradation, alveolar macrophage uptake, and cellular membrane penetration. To address these challenges, various delivery vectors-ranging from viral vectors to non-viral systems such as lipid nanoparticles, polymeric carriers, and hybrid nanomaterials-have been engineered to enhance stability, targeting, and transfection efficiency. This review highlights recent advances in inhalable nucleic acid delivery platforms, discusses the critical physiological and pathological barriers in the pulmonary microenvironment, and outlines current clinical progress. Finally, we explore future directions and challenges toward clinical translation of these innovative therapies. STATEMENT OF SIGNIFICANCE: Chronic pulmonary diseases, including COPD, asthma, IPF, and CF, remain among the leading causes of morbidity and mortality worldwide, with limited treatment options that target disease pathogenesis at the molecular level. Nucleic acid therapeutics offer transformative potential to precisely regulate gene expression, correct mutations, and modulate inflammatory or fibrotic pathways. However, effective delivery to the lungs remains a critical barrier to clinical translation. This review highlights the emerging field of inhalable nucleic acid delivery systems, integrating recent advances in nanocarrier design, pulmonary targeting strategies, and the navigation of biological barriers. By bridging nucleic acid pharmacology with pulmonary drug delivery science, this review provides a comprehensive framework for the rational design and clinical development of next-generation genetic therapies for respiratory diseases. It also offers forward-looking perspectives on overcoming current translational hurdles, thereby accelerating the realization of precision gene therapy for chronic lung disorders.
可吸入核酸药物递送系统作为治疗慢性肺部疾病（如哮喘、慢性阻塞性肺疾病（COPD）、囊性纤维化（CF）和特发性肺纤维化（IPF））的一种有前景的策略，已受到越来越多的关注。这些疾病通常以慢性炎症、气道重塑和进行性肺功能障碍为特征，带来了重大的临床挑战。核酸疗法，包括质粒DNA、信使RNA（mRNA）、微小RNA（miRNA）、小干扰RNA（siRNA）和反义寡核苷酸（ASO），具有纠正基因缺陷、调节异常基因表达或抑制致病信号通路的潜力。吸入途径能够直接、无创地进入肺部，实现局部递送、快速起效并减少全身副作用。然而，肺部存在多种生物屏障，限制了核酸的递送和活性，包括黏液清除、酶降解、肺泡巨噬细胞摄取和细胞膜穿透。为应对这些挑战，人们设计了各种递送载体，从病毒载体到脂质纳米颗粒、聚合物载体和杂化纳米材料等非病毒系统，以提高稳定性、靶向性和转染效率。本综述重点介绍了可吸入核酸递送平台的最新进展，讨论了肺部微环境中的关键生理和病理屏障，并概述了当前的临床进展。最后，我们探讨了这些创新疗法临床转化的未来方向和挑战。重要性声明：包括COPD、哮喘、IPF和CF在内的慢性肺部疾病仍然是全球发病和死亡的主要原因之一，针对疾病发病机制进行分子水平治疗的选择有限。核酸疗法具有精确调节基因表达、纠正突变以及调节炎症或纤维化途径的变革潜力。然而，有效递送至肺部仍然是临床转化的关键障碍。本综述重点介绍了可吸入核酸递送系统这一新兴领域，整合了纳米载体设计、肺部靶向策略以及生物屏障跨越方面的最新进展。通过将核酸药理学与肺部药物递送科学相结合，本综述为合理设计和临床开发下一代呼吸系统疾病基因疗法提供了一个全面的框架。它还对克服当前的转化障碍提供了前瞻性观点，从而加速实现针对慢性肺部疾病的精准基因治疗。
