Biologics-based technologies for highly efficient and targeted RNA delivery

Kostyusheva, A.; Brezgin, S.; Ponomareva, N.; Frolova, A.; Lunin, A.; Bayurova, E.; Tikhonov, A.; Slatinskaya, O.; Demina, P.; Kachanov, A.; Babayeva, G.; Khan, I.; Khochenkov, D.; Khochenkova, Y.; Sokolova, D.; Silachev, D.; Maksimov, G.; Khaydukov, E.; Pokrovsky, V.S.; Zamyatnin, A.A.; Parodi, A.; Gordeychuk, I.; Chulanov, V.; Kostyushev, D.

Авторы: Kostyusheva Anastasiya, Brezgin Sergey, Ponomareva Natalia, Frolova Anastasiia, Lunin Alexander, Bayurova Ekaterina, Tikhonov Andrey, Slatinskaya Olga, Demina Polina, Kachanov Artyom, Babayeva Gulalek, Khan Irina, Khochenkov Dmitry, Khochenkova Yulia, Sokolova Darina, Silachev Denis, Maksimov Georgy, Khaydukov Evgeny, Pokrovsky Vadim S., Zamyatnin Andrey A., Parodi Alessandro, Gordeychuk Ilya, Chulanov Vladimir, Kostyushev Dmitry
Журнал: Molecular Therapy
Том: 33
Номер: 1
Год издания: 2024
Издательство: Nature Publishing Group
Местоположение издательства: United Kingdom
Первая страница: 1
Последняя страница: 16
DOI: 10.1016/j.ymthe.2024.11.004
Аннотация: The demand for RNA-based therapeutics is increasing globally.However, their use is hampered by the lack of safe and effectivedelivery vehicles. Here, we developed technologies for highlyefficient delivery of RNA cargo into programmable extracellular vesicle-mimetic nanovesicles (EMNVs) by fabricatinghybrid EMNV-liposomes (Hybs). Tissue targeting is endowedby highly efficient genetic platforms based on truncatedCD63 (DCD63) or PTGFRN proteins. For the first time wereveal their efficiency in functionalizing EMNVs, resulting in>10-fold enhancement of nanoparticle internalization in vitroand >2-fold in vivo. RNA delivery using Hybs demonstrated efficiency of >85% in human and mouse cell lines. Comparativeanalysis of EMNVs and Hyb lysosome colocalization and stability suggested that Hybs enter the lysosomal compartment andescape over time, whereas EMNVs primarily avoid it. Finally,we used these technologies to generate liver-targeting Hybsloaded 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 widerange of next-generation vehicles for highly efficient, safe delivery of RNA into desired organs and tissues for therapeutic andprophylactic applications.

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Biologics-based technologies for highly efficient and targeted RNA deliveryстатья

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