Eygeris Yulia, Jozic Antony, Henderson Michael I, Nelson Dylan, Sahay Gaurav
Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland OR 97201, USA.
Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Mol Ther Methods Clin Dev. 2025 May 21;33(2):101495. doi: 10.1016/j.omtm.2025.101495. eCollection 2025 Jun 12.
Saponins are a class of phytocompounds known for their amphiphilic properties. Here, we have evaluated incorporation of 40 saponins into a model lipid nanoparticle (LNP) formulation and evaluated their performance and . We reasoned that the surfactant activity of saponins could be beneficial in the context of cell and gene therapy due to the disruption of the intracellular membranes. We established formulation methodology to incorporate saponins into LNPs and measured their endosomal disruption and transfection efficiency with DNA barcode and mRNA cargoes. We identified two saponins-quillaic acid and macranthoidin B-that increase the LNP transfection efficiency and endosomal disruption. Saponin formulations demonstrated cargo-dependent activation of the innate immune system, as measured by the cell-based assays of interferon regulatory factor (IRF) and NF-κB pathway activation. Quillaic acid LNPs resulted in higher titers of anti-OVA IgG2a in the vaccination studies compared to a "naive" LNP control, which suggests a more Th1-biased immunopathology of these vaccines. As Th2-biased vaccines can trigger an allergic response, an mRNA vaccine with a balanced Th1/Th2 response is more favorable for translation into the clinic. Overall, quillaic acid may serve as an adjuvant for mRNA vaccines and potentially decrease the risk of vaccine-associated adverse events.
皂苷是一类以两亲性特性而闻名的植物化合物。在此，我们评估了40种皂苷掺入模型脂质纳米颗粒（LNP）制剂中的情况，并评估了它们的性能。我们推断，由于皂苷具有破坏细胞内膜的作用，其表面活性剂活性在细胞和基因治疗方面可能是有益的。我们建立了将皂苷掺入LNPs的制剂方法，并使用DNA条形码和mRNA货物测量了它们的内体破坏和转染效率。我们鉴定出两种皂苷——齐墩果酸和大花紫薇素B——它们可提高LNP的转染效率和内体破坏能力。通过基于细胞的干扰素调节因子（IRF）和NF-κB途径激活检测发现，皂苷制剂表现出对先天免疫系统的货物依赖性激活。在疫苗接种研究中，与“未处理的”LNP对照相比，齐墩果酸LNP产生了更高滴度的抗OVA IgG2a，这表明这些疫苗具有更偏向Th1的免疫病理学特征。由于偏向Th2的疫苗会引发过敏反应，具有平衡Th1/Th2反应的mRNA疫苗更有利于转化应用于临床。总体而言，齐墩果酸可作为mRNA疫苗的佐剂，并有可能降低疫苗相关不良事件的风险。
