气道上皮细胞特异性递送脂质纳米颗粒负载siRNA用于哮喘治疗
2022/12/21
摘要
背景：小干扰RNA (small interference RNA,siRNA)具有特异性和固有的mRNA裂解活性，被认为是通过抑制气道上皮细胞(AECs)促炎细胞因子的表达和释放来降低哮喘加重率的有前途的治疗方法。为了发挥siRNA药物的治疗作用，需要高效、安全的纳米配方将这些核酸运送到靶细胞。
方法：在此，我们利用新型吸入性脂质纳米颗粒(LNPs)靶向AECs根尖端的细胞间粘附分子-1 (ICAM-1)受体。该传递系统旨在提高siRNA在AECs中的特异性传递效率，以防止AECs中促炎细胞因子的表达及其伴随症状的并行发生。一种类似于鼻病毒部分衣壳蛋白并与ICAM-1受体结合的环状肽最初与胆固醇结合，随后与可电离阳离子脂质组装，形成装载siRNA对抗胸腺基质淋巴生成素(TSLP siRNA)的LNPs (Pep-LNPs)。获得的PepLNPs在体外和体内进行了彻底的表征和评估。
结果：Pep-LNPs在体外表达ICAM-1的人上皮细胞中显著增强细胞摄取和基因沉默效率，表现出AEC特异性递送，并改善卵白蛋白激发哮喘小鼠肺给药后的基因沉默效果。更重要的是，Pep-LNPs显著下调AECs中TSLP的表达，有效缓解炎症细胞浸润，并减少哮喘小鼠中IL-4、IL-13等其他促炎细胞因子的分泌和粘液的产生。
结论：这项研究表明，Pep-LNPs安全有效地将siRNA药物输送到AECs内，并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。
Airway epithelial cell-specific delivery of lipid nanoparticles loading siRNA for asthma treatment
M. J. Zhang, H. Y. Jiang, L. Wu, H. Y. Lu, H. Bera, X. Zhao, et al
Abstract
BACKGROUND: 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, nanoformulations with high efficiency and safety are required to deliver these nucleic acids to the target cells.
METHODS: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 PepLNPs were subjected to thorough characterization and evaluations in vitro and in vivo.
RESULTS: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.
CONCLUSIONS: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.
背景：小干扰RNA (small interference RNA,siRNA)具有特异性和固有的mRNA裂解活性，被认为是通过抑制气道上皮细胞(AECs)促炎细胞因子的表达和释放来降低哮喘加重率的有前途的治疗方法。为了发挥siRNA药物的治疗作用，需要高效、安全的纳米配方将这些核酸运送到靶细胞。
方法：在此，我们利用新型吸入性脂质纳米颗粒(LNPs)靶向AECs根尖端的细胞间粘附分子-1 (ICAM-1)受体。该传递系统旨在提高siRNA在AECs中的特异性传递效率，以防止AECs中促炎细胞因子的表达及其伴随症状的并行发生。一种类似于鼻病毒部分衣壳蛋白并与ICAM-1受体结合的环状肽最初与胆固醇结合，随后与可电离阳离子脂质组装，形成装载siRNA对抗胸腺基质淋巴生成素(TSLP siRNA)的LNPs (Pep-LNPs)。获得的PepLNPs在体外和体内进行了彻底的表征和评估。
结果：Pep-LNPs在体外表达ICAM-1的人上皮细胞中显著增强细胞摄取和基因沉默效率，表现出AEC特异性递送，并改善卵白蛋白激发哮喘小鼠肺给药后的基因沉默效果。更重要的是，Pep-LNPs显著下调AECs中TSLP的表达，有效缓解炎症细胞浸润，并减少哮喘小鼠中IL-4、IL-13等其他促炎细胞因子的分泌和粘液的产生。
结论：这项研究表明，Pep-LNPs安全有效地将siRNA药物输送到AECs内，并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。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Journal of Controlled Release, 2022, 352: 422-437 DOI: 10.1016/j.jconrel.2022.10.020）
Airway epithelial cell-specific delivery of lipid nanoparticles loading siRNA for asthma treatment
M. J. Zhang, H. Y. Jiang, L. Wu, H. Y. Lu, H. Bera, X. Zhao, et al
Abstract
BACKGROUND: 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, nanoformulations with high efficiency and safety are required to deliver these nucleic acids to the target cells.
METHODS: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 PepLNPs were subjected to thorough characterization and evaluations in vitro and in vivo.
RESULTS: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.
CONCLUSIONS: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.
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