Department of Biomaterials and Biomedical Technology, University Medical Center Groningen (UMCG), The Personalized Medicine Research Institute (PRECISION), University of Groningen, Ant. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, FI-00014, Finland.
Nat Commun. 2024 Jun 26;15(1):5398. doi: 10.1038/s41467-024-49804-x.
Ionotropic gelation is widely used to fabricate targeting nanoparticles (NPs) with polysaccharides, leveraging their recognition by specific lectins. Despite the fabrication scheme simply involves self-assembly of differently charged components in a straightforward manner, the identification of a potent combinatory formulation is usually limited by structural diversity in compound collections and trivial screen process, imposing crucial challenges for efficient formulation design and optimization. Herein, we report a diversity-oriented combinatory formulation screen scheme to identify potent gene delivery cargo in the context of precision cardiac therapy. Distinct categories of cationic compounds are tested to construct RNA delivery system with an ionic polysaccharide framework, utilizing a high-throughput microfluidics workstation coupled with streamlined NPs characterization system in an automatic, step-wise manner. Sequential computational aided interpretation provides insights in formulation optimization in a broader scenario, highlighting the usefulness of compound library diversity. As a result, the out-of-bag NPs, termed as GluCARDIA NPs, are utilized for loading therapeutic RNA to ameliorate cardiac reperfusion damages and promote the long-term prognosis. Overall, this work presents a generalizable formulation design strategy for polysaccharides, offering design principles for combinatory formulation screen and insights for efficient formulation identification and optimization.
离子凝胶化广泛用于通过多糖来制备靶向纳米颗粒 (NPs)，利用它们与特定凝集素的识别。尽管制造方案简单地涉及以直接的方式将带不同电荷的成分自组装，但强力组合配方的识别通常受到化合物库中结构多样性和琐碎筛选过程的限制，这对有效配方设计和优化构成了关键挑战。在此，我们报告了一种多样性导向的组合配方筛选方案，以在精准心脏治疗的背景下确定有效的基因传递载体。使用高通量微流控工作站并结合自动、逐步的精简 NPs 表征系统，测试了不同类别的阳离子化合物，以构建带有离子多糖骨架的 RNA 递送系统。顺序的计算辅助解释为更广泛的方案中的配方优化提供了见解，突出了化合物库多样性的有用性。结果，这些作为 GluCARDIA NPs 的外袋 NPs 被用于负载治疗性 RNA，以改善心脏再灌注损伤并促进长期预后。总的来说，这项工作为多糖提供了一种可推广的配方设计策略，为组合配方筛选提供了设计原则，并为有效配方的识别和优化提供了见解。
