Wuya College of Innovation, Shenyang Pharmaceutical University, Wenhua Road No. 103, 110016 Shenyang, China; School of Pharmacy, Henan University, Kaifeng 475004, China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Wenhua Road No. 103, 110016 Shenyang, China.
Adv Drug Deliv Rev. 2023 Dec;203:115144. doi: 10.1016/j.addr.2023.115144. Epub 2023 Nov 22.
In recent years, RNA-based therapies have gained much attention as biomedicines due to their remarkable therapeutic effects with high specificity and potency. Lung diseases offer a variety of currently undruggable but attractive targets that could potentially be treated with RNA drugs. Inhaled RNA drugs for the treatment of lung diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, and acute respiratory distress syndrome, have attracted more and more attention. A variety of novel nanoformulations have been designed and attempted for the delivery of RNA drugs to the lung via inhalation. However, the delivery of RNA drugs via inhalation poses several challenges. It includes protection of the stability of RNA molecules, overcoming biological barriers such as mucus and cell membrane to the delivery of RNA molecules to the targeted cytoplasm, escaping endosomal entrapment, and circumventing unwanted immune response etc. To address these challenges, ongoing researches focus on developing innovative nanoparticles to enhance the stability of RNA molecules, improve cellular targeting, enhance cellular uptake and endosomal escape to achieve precise delivery of RNA drugs to the intended lung cells while avoiding unwanted nano-bio interactions and off-target effects. The present review first addresses the pathologic hallmarks of different lung diseases, disease-related cell types in the lung, and promising therapeutic targets in these lung cells. Subsequently we highlight the importance of the nano-bio interactions in the lung that need to be addressed to realize disease-related cell-specific delivery of inhaled RNA drugs. This is followed by a review on the physical and chemical characteristics of inhaled nanoformulations that influence the nano-bio interactions with a focus on surface functionalization. Finally, the challenges in the development of inhaled nanomedicines and some key aspects that need to be considered in the development of future inhaled RNA drugs are discussed.
近年来，基于 RNA 的疗法作为生物药物引起了广泛关注，因为它们具有高度特异性和效力的显著治疗效果。肺部疾病提供了多种目前无法治疗但具有吸引力的靶点，这些靶点可能可以用 RNA 药物治疗。用于治疗肺部疾病（包括哮喘、慢性阻塞性肺疾病、囊性纤维化和急性呼吸窘迫综合征）的吸入式 RNA 药物越来越受到关注。已经设计并尝试了多种新型纳米制剂，通过吸入将 RNA 药物递送至肺部。然而，通过吸入递送至肺部的 RNA 药物存在一些挑战。它包括保护 RNA 分子的稳定性、克服生物屏障（如黏液和细胞膜）以将 RNA 分子递送至靶细胞质、逃避内体捕获以及避免不必要的免疫反应等。为了解决这些挑战，正在进行的研究集中于开发创新的纳米粒子，以增强 RNA 分子的稳定性、改善细胞靶向、增强细胞摄取和内体逃逸，从而实现 RNA 药物精确递送至预期的肺部细胞，同时避免不必要的纳米-生物相互作用和脱靶效应。本综述首先介绍了不同肺部疾病的病理特征、肺部中的疾病相关细胞类型以及这些肺部细胞中的有前途的治疗靶点。随后，我们强调了在肺部中纳米-生物相互作用的重要性，需要解决这些相互作用，以实现吸入式 RNA 药物对疾病相关细胞的特异性递送。接着，我们回顾了影响纳米-生物相互作用的吸入式纳米制剂的物理和化学特性，重点关注表面功能化。最后，讨论了吸入型纳米药物开发中的挑战以及开发未来吸入型 RNA 药物需要考虑的一些关键方面。
