Zhang Mengjun, Jiang Huiyang, Wu Lan, Lu Haoyu, Bera Hriday, Zhao Xing, Guo Xiong, Liu Xulu, Cun Dongmei, Yang Mingshi
Wuya College of Innovation, Shenyang Pharmaceutical University, Wenhua Road, No. 103, 110016 Shenyang, China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Wenhua Road, No. 103, 110016 Shenyang, China; Dr. B.C. Roy College of Pharmacy & Allied Health Sciences, Durgapur, West Bengal, 713212, India.
J Control Release. 2022 Dec;352:422-437. doi: 10.1016/j.jconrel.2022.10.020. Epub 2022 Oct 31.
With specific and inherent mRNA cleaving activity, small interfering RNA (siRNA) has been deemed promising therapeutics to reduce the exacerbation rate of asthma by inhibiting the expression and release of proinflammatory cytokines from airway epithelial cells (AECs). To exert the therapeutic effects of siRNA drugs, nano-formulations with high efficiency and safety are required to deliver these nucleic acids to the target cells. Herein, we exploited novel inhaled lipid nanoparticles (LNPs) targeting intercellular adhesion molecule-1 (ICAM-1) receptors on the apical side of AECs. This delivery system is meant to enhance the specific delivery efficiency of siRNA in AECs to prevent the expression of proinflammatory cytokines in AECs and the concomitant symptoms in parallel. A cyclic peptide that resembles part of the capsid protein of rhinovirus and binds to ICAM-1 receptors was initially conjugated with cholesterol and subsequently assembled with ionizable cationic lipids to form the LNPs (Pep-LNPs) loaded with siRNA against thymic stromal lymphopoietin (TSLP siRNA). The obtained Pep-LNPs were subjected to thorough characterization and evaluations in vitro and in vivo. Pep-LNPs significantly enhanced cellular uptake and gene silencing efficiency in human epithelial cells expressing ICAM-1 in vitro, exhibited AEC-specific delivery and improved the gene silencing effect in ovalbumin-challenged asthmatic mice after pulmonary administration. More importantly, Pep-LNPs remarkably downregulated the expression of TSLP in AECs, effectively alleviated inflammatory cell infiltration, and reduced the secretion of other proinflammatory cytokines, including IL-4 and IL-13, as well as mucus production in asthmatic mice. This study demonstrates that Pep-LNPs are safe and efficient to deliver siRNA drugs to asthmatic AECs and could potentially alleviate allergic asthma by inhibiting the overexpression of proinflammatory cytokines in the airway.
小干扰RNA（siRNA）具有特异性和内在的mRNA切割活性，已被视为一种有前景的治疗药物，可通过抑制气道上皮细胞（AECs）中促炎细胞因子的表达和释放来降低哮喘的恶化率。为了发挥siRNA药物的治疗效果，需要高效且安全的纳米制剂将这些核酸递送至靶细胞。在此，我们开发了新型吸入脂质纳米颗粒（LNPs），其靶向AECs顶端侧的细胞间粘附分子-1（ICAM-1）受体。该递送系统旨在提高siRNA在AECs中的特异性递送效率，以防止AECs中促炎细胞因子的表达及随之而来的症状。一种类似于鼻病毒衣壳蛋白部分且与ICAM-1受体结合的环肽，最初与胆固醇偶联，随后与可电离阳离子脂质组装形成负载抗胸腺基质淋巴细胞生成素的siRNA（TSLP siRNA）的LNPs（Pep-LNPs）。对获得的Pep-LNPs进行了全面的体外和体内表征及评估。Pep-LNPs在体外显著增强了在表达ICAM-1的人上皮细胞中的细胞摄取和基因沉默效率，在肺部给药后，在卵清蛋白激发的哮喘小鼠中表现出AEC特异性递送并改善了基因沉默效果。更重要的是，Pep-LNPs显著下调了AECs中TSLP的表达，有效减轻了炎症细胞浸润，并减少了包括IL-4和IL-13在内的其他促炎细胞因子的分泌以及哮喘小鼠中的黏液产生。本研究表明，Pep-LNPs将siRNA药物递送至哮喘AECs是安全且有效的，并且可能通过抑制气道中促炎细胞因子的过表达来缓解过敏性哮喘。
