PDF(Pubmed)
Abstract：
Nanoparticle-mediated mRNA delivery has emerged as a promising therapeutic modality, but its growth is still limited by the discovery and optimization of effective and well-tolerated delivery strategies. Lipid nanoparticles containing charged or ionizable lipids are an emerging standard for in vivo mRNA delivery, so creating facile, tunable strategies to synthesize these key lipid-like molecules is essential to advance the field. Here, we generate a library of N-substituted glycine oligomers, peptoids, and undertake a multistage down-selection process to identify lead candidate peptoids as the ionizable component in our Nutshell nanoparticle platform. First, we identify a promising peptoid structural motif by clustering a library of >200 molecules based on predicted physical properties and evaluate members of each cluster for reporter gene expression in vivo. Then, the lead peptoid motif is optimized using design of experiments methodology to explore variations on the charged and lipophilic portions of the peptoid, facilitating the discovery of trends between structural elements and nanoparticle properties. We further demonstrate that peptoid-based Nutshells leads to expression of therapeutically relevant levels of an anti-respiratory syncytial virus antibody in mice with minimal tolerability concerns or induced immune responses compared to benchmark ionizable lipid, DLin-MC3-DMA. Through this work, we present peptoid-based nanoparticles as a tunable delivery platform that can be optimized toward a range of therapeutic programs.
摘要：
纳米颗粒介导的mRNA递送已成为一种有前途的治疗方式，但它的增长仍然受到有效和耐受性良好的交付策略的发现和优化的限制。含有带电或可电离脂质的脂质纳米颗粒是体内mRNA递送的新兴标准，所以创造便利，合成这些关键类脂分子的可调策略对于推进该领域至关重要。这里,我们产生了一个N-取代的甘氨酸寡聚体文库,peptoids,并进行多阶段向下选择过程，以在我们的果壳纳米颗粒平台中确定前导候选肽作为电离成分。首先,我们通过基于预测的物理性质对>200个分子的文库进行聚类来鉴定有希望的类肽结构基序,并评估每个簇的成员在体内的报告基因表达。然后，铅类肽基序使用实验设计方法进行优化，以探索类肽的带电和亲脂性部分的变化，有利于发现结构元素和纳米颗粒性质之间的趋势。我们进一步证明，与基准可电离脂质相比，基于类肽的果壳导致小鼠中治疗相关水平的抗呼吸道合胞病毒抗体表达，耐受性问题或诱导的免疫反应最小。DLin-MC3-DMA。通过这项工作,我们提出了基于类肽的纳米颗粒作为一个可调的递送平台，可以针对一系列治疗方案进行优化。
