Mucus forms the first defense line of human lungs, and as such hampers the efficient delivery of therapeutics to the underlying epithelium. This holds particularly true for genetic cargo such as CRISPR-based gene editing tools which cannot readily surmount the mucosal barrier. While lipid nanoparticles (LNPs) emerge as versatile non-viral gene delivery systems that can help overcome the delivery challenge, many knowledge gaps remain, especially for diseased states such as cystic fibrosis (CF). This study provides fundamental insights into Cas9 mRNA or ribonucleoprotein-loaded LNP-mucus interactions in healthy and diseased states by assessing the impact of the genetic cargo, mucin sialylation, mucin concentration, ionic strength, pH, and polyethylene glycol (PEG) concentration and nature on LNP diffusivity leveraging experimental approaches and Brownian dynamics (BD) simulations. Taken together, this study identifies key mucus and LNP characteristics that are critical to enabling a rational LNP design for transmucosal delivery.

中文翻译：

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探索健康和囊性纤维化条件下脂质纳米颗粒-粘液相互作用的机制

粘液形成了人类肺部的第一道防线，因此阻碍了治疗药物向下面的上皮细胞的有效输送。对于基因货物尤其如此，例如基于 CRISPR 的基因编辑工具，它们无法轻易跨越粘膜屏障。虽然脂质纳米粒子（LNP）作为通用的非病毒基因传递系统出现，可以帮助克服传递挑战，但仍然存在许多知识差距，特别是对于囊性纤维化（CF）等疾病状态。这项研究通过评估遗传货物、粘蛋白唾液酸化、粘蛋白浓度、离子强度、pH 值和聚乙二醇 (PEG) 浓度和性质的影响，为健康和患病状态下 Cas9 mRNA 或核糖核蛋白负载的 LNP-粘液相互作用提供了基本见解。利用实验方法和布朗动力学 (BD) 模拟研究 LNP 扩散率。总而言之，这项研究确定了关键的粘液和 LNP 特征，这些特征对于实现合理的 LNP 跨粘膜递送设计至关重要。