Comparative optimization of polysaccharide-based nanoformulations for cardiac RNAi therapy

Han Gao, Sen Li, Zhengyi Lan, Da Pan, Gonna Somu Naidu, Dan Peer, Chenyi Ye, Hangrong Chen, Ming Ma (), Zehua Liu () and Hélder A. Santos ()
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Han Gao: University Medical Center Groningen (UMCG), The Personalized Medicine Research Institute (PRECISION), University of Groningen
Sen Li: Zhejiang University School of Medicine
Zhengyi Lan: Chinese Academy of Sciences
Da Pan: Southeast University
Gonna Somu Naidu: Tel Aviv University
Dan Peer: Tel Aviv University
Chenyi Ye: Zhejiang University School of Medicine
Hangrong Chen: Chinese Academy of Sciences
Ming Ma: Chinese Academy of Sciences
Zehua Liu: University Medical Center Groningen (UMCG), The Personalized Medicine Research Institute (PRECISION), University of Groningen
Hélder A. Santos: University Medical Center Groningen (UMCG), The Personalized Medicine Research Institute (PRECISION), University of Groningen

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49804-x

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