Biologics-based technologies for highly efficient and targeted RNA delivery.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Molecular Therapy Pub Date : 2024-11-06 DOI:10.1016/j.ymthe.2024.11.004
Anastasiya Kostyusheva, Sergey Brezgin, Natalia Ponomareva, Anastasiia Frolova, Alexander Lunin, Ekaterina Bayurova, Andrey Tikhonov, Olga Slatinskaya, Polina Demina, Artyom Kachanov, Gulalek Babayeva, Irina Khan, Dmitry Khochenkov, Yulia Khochenkova, Darina Sokolova, Denis Silachev, Georgy Maksimov, Evgeny Khaydukov, Vadim S Pokrovsky, Andrey A Zamyatnin, Alessandro Parodi, Ilya Gordeychuk, Vladimir Chulanov, Dmitry Kostyushev
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Abstract

The demand for RNA-based therapeutics is increasing globally. However, their use is hampered by the lack of safe and effective delivery vehicles. Here, we developed technologies for highly efficient delivery of RNA cargo into programmable extracellular vesicle-mimetic nanovesicles (EMNVs) by fabricating hybrid EMNV-liposomes (Hybs). Tissue targeting is endowed by highly efficient genetic platforms based on truncated CD63 (ΔCD63) or PTGFRN proteins. For the first time we reveal their efficiency in functionalizing EMNVs, resulting in >10-fold enhancement of nanoparticle internalization in vitro and >2-fold in vivo. RNA delivery using Hybs demonstrated efficiency of >85% in human and mouse cell lines. Comparative analysis of EMNVs and Hyb lysosome colocalization and stability suggested that Hybs enter the lysosomal compartment and escape over time, whereas EMNVs primarily avoid it. Finally, we used these technologies to generate liver-targeting Hybs loaded with therapeutic small interfering RNA and demonstrated the robust efficiency of this system in vitro and in vivo. These technologies can be adapted for manufacturing a wide range of next-generation vehicles for highly efficient, safe delivery of RNA into desired organs and tissues for therapeutic and prophylactic applications.

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基于生物制剂的高效定向 RNA 输送技术。
全球对基于 RNA 的疗法的需求日益增长。然而,由于缺乏安全有效的运载工具,这些药物的使用受到了阻碍。在这里,我们通过制造混合EMNVs-脂质体(Hyb),开发了将RNA货物高效输送到可编程细胞外囊泡模拟纳米囊泡(EMNV)的技术。组织靶向由基于截短的CD63(ΔCD63)或PTGFRN蛋白的高效基因平台赋予。我们首次揭示了它们对 EMNV 的功能化效率,其结果是 NP 体外内化增强了 10 倍以上,体内增强了 2 倍以上。在人类和小鼠细胞系中,使用 Hyb 递送 RNA 的效率大于 85%。对 EMNVs 和 Hyb 溶酶体共定位和稳定性的比较分析表明,Hyb 进入溶酶体并随着时间的推移而逃逸,而 EMNVs 则主要避开溶酶体。最后,我们利用这些技术生成了装载有治疗 siRNA 的肝脏靶向 Hyb,并在体外和体内证明了这一系统的高效性。这些技术可用于制造各种下一代载体,以高效、安全地将 RNA 运送到所需器官和组织,用于治疗和预防。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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