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siRNA release kinetics from polymeric nanoparticles correlate with RNAi efficiency and inflammation therapy via oral delivery.
Acta Biomaterialia ( IF 9.4 ) Pub Date : 2019-12-06 , DOI: 10.1016/j.actbio.2019.12.005 Chunbai He 1 , Haimei Yue 1 , Lu Xu 1 , Yifu Liu 1 , Yudong Song 1 , Cui Tang 1 , Chunhua Yin 1
Acta Biomaterialia ( IF 9.4 ) Pub Date : 2019-12-06 , DOI: 10.1016/j.actbio.2019.12.005 Chunbai He 1 , Haimei Yue 1 , Lu Xu 1 , Yifu Liu 1 , Yudong Song 1 , Cui Tang 1 , Chunhua Yin 1
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Despite many efforts in the rational design of nanoparticles (NPs) to overcome the biological barriers to small interfering RNA (siRNA) delivery for improving gene silencing efficiency, little is known about the correlations between siRNA release kinetics and RNA interference (RNAi) efficiency and inflammation therapy via oral delivery. On the basis of mannose-modified trimethyl chitosan-cysteine (MTC) polymers, seven types of MTC NPs containing tumor necrosis factor (TNF)-α siRNA were prepared through ionic gelation. The siRNA release kinetics from MTC NPs were finely tuned by adjusting the kinds and amounts of the crosslinkers involved. These MTC NPs exhibited no disparities in siRNA protection against enzymatic degradation in physiological fluids and cellular uptake in macrophages; however, they showed distinct in vitro siRNA release profiles and intracellular unpacking kinetics. MTC NPs with relatively rapid and sustained siRNA release were responsible for efficient, prompt, and prolonged RNAi, contributing to desired therapeutic efficacy in acute and chronic inflammatory murine models following oral delivery. However, MTC NPs insufficiently releasing siRNA could not elicit effective RNAi. Collectively, the present investigation might provide broad insights into the optimization of siRNA nanocarriers with respect to their release kinetics for improving RNAi efficacies aiming at different types of inflammatory diseases. STATEMENT OF SIGNIFICANCE: siRNA release kinetics in the cytoplasm and pathological characteristics of diseases themselves determine the therapeutic efficacy of siRNA delivery. Herein, by adjusting the kinds and amounts of the crosslinkers involved, we developed seven types of MTC NPs containing TNF-α siRNA with distinct siRNA release kinetics. MTC NPs with relatively rapid and sustained siRNA release were responsible for prompt and prolonged RNAi, respectively, contributing to desired therapeutic efficacy in acute and chronic inflammation following oral delivery. These results might provide broad insights into the optimization of siRNA nanocarriers in respect to their release kinetics for improving therapeutic outcomes toward different clinical requirements.
中文翻译：
siRNA从聚合物纳米颗粒释放的动力学与RNAi效率和通过口服给药进行的炎症治疗有关。
尽管在纳米粒子（NPs）的合理设计方面做出了许多努力，以克服小干扰RNA（siRNA）传递以提高基因沉默效率的生物学障碍，但对siRNA释放动力学与RNA干扰（RNAi）效率与炎症之间的相关性知之甚少通过口服给药进行治疗。基于甘露糖修饰的三甲基壳聚糖-半胱氨酸（MTC）聚合物，通过离子凝胶法制备了七种类型的包含肿瘤坏死因子（TNF）-αsiRNA的MTC NP。通过调节所涉及的交联剂的种类和数量，可以很好地调节MTC NP的siRNA释放动力学。这些MTC NP在针对生理液中酶促降解和巨噬细胞摄取的siRNA保护中没有表现出差异。然而，它们显示出独特的体外siRNA释放曲线和细胞内拆包动力学。具有相对快速且持续的siRNA释放的MTC NP负责有效，迅速和延长的RNAi，有助于口服给药后在急性和慢性炎症小鼠模型中产生所需的治疗功效。但是，MTC NPs不能充分释放siRNA不能引发有效的RNAi。总体而言，目前的研究可能为优化siRNA纳米载体的释放动力学提供广泛的见解，以提高针对不同类型炎症性疾病的RNAi效率。意义声明：siRNA在细胞质中的释放动力学和疾病本身的病理特征决定了siRNA递送的治疗功效。在此处，通过调整所涉及的交联剂的种类和数量，我们开发了七种MTC NP，它们包含具有不同siRNA释放动力学的TNF-αsiRNA。具有相对快速和持续的siRNA释放的MTC NP分别导致迅速和长期的RNAi，从而在口服给药后对急性和慢性炎症产生所需的治疗功效。这些结果可能为优化siRNA纳米载体的释放动力学提供广泛的见解，以改善针对不同临床需求的治疗效果。有助于口服给药后在急性和慢性炎症中的所需治疗功效。这些结果可能为优化siRNA纳米载体的释放动力学提供广泛的见解，以改善针对不同临床需求的治疗效果。有助于口服给药后在急性和慢性炎症中的所需治疗功效。这些结果可能为优化siRNA纳米载体的释放动力学提供广泛的见解，以改善针对不同临床需求的治疗效果。
更新日期：2019-12-06
中文翻译：
siRNA从聚合物纳米颗粒释放的动力学与RNAi效率和通过口服给药进行的炎症治疗有关。
尽管在纳米粒子（NPs）的合理设计方面做出了许多努力，以克服小干扰RNA（siRNA）传递以提高基因沉默效率的生物学障碍，但对siRNA释放动力学与RNA干扰（RNAi）效率与炎症之间的相关性知之甚少通过口服给药进行治疗。基于甘露糖修饰的三甲基壳聚糖-半胱氨酸（MTC）聚合物，通过离子凝胶法制备了七种类型的包含肿瘤坏死因子（TNF）-αsiRNA的MTC NP。通过调节所涉及的交联剂的种类和数量，可以很好地调节MTC NP的siRNA释放动力学。这些MTC NP在针对生理液中酶促降解和巨噬细胞摄取的siRNA保护中没有表现出差异。然而，它们显示出独特的体外siRNA释放曲线和细胞内拆包动力学。具有相对快速且持续的siRNA释放的MTC NP负责有效，迅速和延长的RNAi，有助于口服给药后在急性和慢性炎症小鼠模型中产生所需的治疗功效。但是，MTC NPs不能充分释放siRNA不能引发有效的RNAi。总体而言，目前的研究可能为优化siRNA纳米载体的释放动力学提供广泛的见解，以提高针对不同类型炎症性疾病的RNAi效率。意义声明：siRNA在细胞质中的释放动力学和疾病本身的病理特征决定了siRNA递送的治疗功效。在此处，通过调整所涉及的交联剂的种类和数量，我们开发了七种MTC NP，它们包含具有不同siRNA释放动力学的TNF-αsiRNA。具有相对快速和持续的siRNA释放的MTC NP分别导致迅速和长期的RNAi，从而在口服给药后对急性和慢性炎症产生所需的治疗功效。这些结果可能为优化siRNA纳米载体的释放动力学提供广泛的见解，以改善针对不同临床需求的治疗效果。有助于口服给药后在急性和慢性炎症中的所需治疗功效。这些结果可能为优化siRNA纳米载体的释放动力学提供广泛的见解，以改善针对不同临床需求的治疗效果。有助于口服给药后在急性和慢性炎症中的所需治疗功效。这些结果可能为优化siRNA纳米载体的释放动力学提供广泛的见解，以改善针对不同临床需求的治疗效果。
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