Nano-ghosts: Novel biomimetic nano-vesicles for the delivery of antisense oligonucleotides

Jacopo Oieni; Andrea Lolli; Domenico D'Atri; Nicole Kops; Avner Yayon; Gerjo J.V.M. van Osch; Marcelle Machluf

doi:10.1016/j.jconrel.2021.03.018

Nano-ghosts: Novel biomimetic nano-vesicles for the delivery of antisense oligonucleotides

Jacopo Oieni, Andrea Lolli, Domenico D'Atri, Nicole Kops, Avner Yayon, Gerjo J.V.M. van Osch, Marcelle Machluf^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

15 Citations (Scopus)

Abstract

Antisense oligonucleotides (ASOs) carry an enormous therapeutic potential in different research areas, however, the lack of appropriate carriers for their delivery to the target tissues is hampering their clinical translation. The present study investigates the application of novel biomimetic nano-vesicles, Nano-Ghosts (NGs), for the delivery of ASOs to human mesenchymal stem cells (MSCs), using a microRNA inhibitor (antimiR) against miR-221 as proof-of-concept. The integration of this approach with a hyaluronic acid-fibrin (HA-FB) hydrogel scaffold is also studied, thus expanding the potential of NGs applications in regenerative medicine. The study shows robust antimiR encapsulation in the NGs using electroporation and the NGs ability to be internalized in MSCs and to deliver their cargo while avoiding endo-lysosomal degradation. This leads to rapid and strong knock-down of miR-221 in hMSCs in vitro, both in 2D and 3D hydrogel culture conditions (>90% and > 80% silencing efficiency, respectively). Finally, in vivo studies performed with an osteochondral defect model demonstrate the NGs ability to effectively deliver antimiR to endogenous cells. Altogether, these results prove that the NGs can operate as stand-alone system or as integrated platform in combination with scaffolds for the delivery of ASOs for a wide range of applications in drug delivery and regenerative medicine.

Original language	English
Pages (from-to)	28-40
Number of pages	13
Journal	Journal of Controlled Release
Volume	333
Early online date	16 Mar 2021
DOIs	https://doi.org/10.1016/j.jconrel.2021.03.018
Publication status	Published - 10 May 2021

Bibliographical note

Funding Information:
This work was supported by the European Union‘s Horizon 2020 research and innovation program under Marie Sklodowska Curie grant agreement No. 642414 . The authors wish to thank Dr. Nitsan Dahan and Dr. Yael Lupu-Haber for assistance in microscopy and high content analysis studies.

Funding Information:
The author M.M. is the inventor of a patent owned by the Technion Research and Development Foundation Ltd. (a subsidiary of the Technion IIT) entitled ?liposomal compositions and uses of same? that includes concepts presented here and which was granted in the US (US 9,642,817 B2) and the EU (EP 2470164 B1), and which is pending registration in China (CN 102596179) and India (484/ MUMNP/2012). Prof. Avner Yayon is CEO of ProCore Bio Med Ltd. that commercializes the FB/HA hydrogel (FB/HA; RegenoGel?) used in this work. The other authors have no conflict of interest.This work was supported by the European Union?s Horizon 2020 research and innovation program under Marie Sklodowska Curie grant agreement No. 642414. The authors wish to thank Dr. Nitsan Dahan and Dr. Yael Lupu-Haber for assistance in microscopy and high content analysis studies.

Publisher Copyright:
© 2021

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title = "Nano-ghosts: Novel biomimetic nano-vesicles for the delivery of antisense oligonucleotides",

abstract = "Antisense oligonucleotides (ASOs) carry an enormous therapeutic potential in different research areas, however, the lack of appropriate carriers for their delivery to the target tissues is hampering their clinical translation. The present study investigates the application of novel biomimetic nano-vesicles, Nano-Ghosts (NGs), for the delivery of ASOs to human mesenchymal stem cells (MSCs), using a microRNA inhibitor (antimiR) against miR-221 as proof-of-concept. The integration of this approach with a hyaluronic acid-fibrin (HA-FB) hydrogel scaffold is also studied, thus expanding the potential of NGs applications in regenerative medicine. The study shows robust antimiR encapsulation in the NGs using electroporation and the NGs ability to be internalized in MSCs and to deliver their cargo while avoiding endo-lysosomal degradation. This leads to rapid and strong knock-down of miR-221 in hMSCs in vitro, both in 2D and 3D hydrogel culture conditions (>90% and > 80% silencing efficiency, respectively). Finally, in vivo studies performed with an osteochondral defect model demonstrate the NGs ability to effectively deliver antimiR to endogenous cells. Altogether, these results prove that the NGs can operate as stand-alone system or as integrated platform in combination with scaffolds for the delivery of ASOs for a wide range of applications in drug delivery and regenerative medicine.",

author = "Jacopo Oieni and Andrea Lolli and Domenico D'Atri and Nicole Kops and Avner Yayon and {van Osch}, {Gerjo J.V.M.} and Marcelle Machluf",

note = "Funding Information: This work was supported by the European Union{\textquoteleft}s Horizon 2020 research and innovation program under Marie Sklodowska Curie grant agreement No. 642414 . The authors wish to thank Dr. Nitsan Dahan and Dr. Yael Lupu-Haber for assistance in microscopy and high content analysis studies. Funding Information: The author M.M. is the inventor of a patent owned by the Technion Research and Development Foundation Ltd. (a subsidiary of the Technion IIT) entitled ?liposomal compositions and uses of same? that includes concepts presented here and which was granted in the US (US 9,642,817 B2) and the EU (EP 2470164 B1), and which is pending registration in China (CN 102596179) and India (484/ MUMNP/2012). Prof. Avner Yayon is CEO of ProCore Bio Med Ltd. that commercializes the FB/HA hydrogel (FB/HA; RegenoGel?) used in this work. The other authors have no conflict of interest.This work was supported by the European Union?s Horizon 2020 research and innovation program under Marie Sklodowska Curie grant agreement No. 642414. The authors wish to thank Dr. Nitsan Dahan and Dr. Yael Lupu-Haber for assistance in microscopy and high content analysis studies. Publisher Copyright: {\textcopyright} 2021",

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doi = "10.1016/j.jconrel.2021.03.018",

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AU - Oieni, Jacopo

AU - Lolli, Andrea

AU - D'Atri, Domenico

AU - Kops, Nicole

AU - Yayon, Avner

AU - van Osch, Gerjo J.V.M.

AU - Machluf, Marcelle

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PY - 2021/5/10

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N2 - Antisense oligonucleotides (ASOs) carry an enormous therapeutic potential in different research areas, however, the lack of appropriate carriers for their delivery to the target tissues is hampering their clinical translation. The present study investigates the application of novel biomimetic nano-vesicles, Nano-Ghosts (NGs), for the delivery of ASOs to human mesenchymal stem cells (MSCs), using a microRNA inhibitor (antimiR) against miR-221 as proof-of-concept. The integration of this approach with a hyaluronic acid-fibrin (HA-FB) hydrogel scaffold is also studied, thus expanding the potential of NGs applications in regenerative medicine. The study shows robust antimiR encapsulation in the NGs using electroporation and the NGs ability to be internalized in MSCs and to deliver their cargo while avoiding endo-lysosomal degradation. This leads to rapid and strong knock-down of miR-221 in hMSCs in vitro, both in 2D and 3D hydrogel culture conditions (>90% and > 80% silencing efficiency, respectively). Finally, in vivo studies performed with an osteochondral defect model demonstrate the NGs ability to effectively deliver antimiR to endogenous cells. Altogether, these results prove that the NGs can operate as stand-alone system or as integrated platform in combination with scaffolds for the delivery of ASOs for a wide range of applications in drug delivery and regenerative medicine.

AB - Antisense oligonucleotides (ASOs) carry an enormous therapeutic potential in different research areas, however, the lack of appropriate carriers for their delivery to the target tissues is hampering their clinical translation. The present study investigates the application of novel biomimetic nano-vesicles, Nano-Ghosts (NGs), for the delivery of ASOs to human mesenchymal stem cells (MSCs), using a microRNA inhibitor (antimiR) against miR-221 as proof-of-concept. The integration of this approach with a hyaluronic acid-fibrin (HA-FB) hydrogel scaffold is also studied, thus expanding the potential of NGs applications in regenerative medicine. The study shows robust antimiR encapsulation in the NGs using electroporation and the NGs ability to be internalized in MSCs and to deliver their cargo while avoiding endo-lysosomal degradation. This leads to rapid and strong knock-down of miR-221 in hMSCs in vitro, both in 2D and 3D hydrogel culture conditions (>90% and > 80% silencing efficiency, respectively). Finally, in vivo studies performed with an osteochondral defect model demonstrate the NGs ability to effectively deliver antimiR to endogenous cells. Altogether, these results prove that the NGs can operate as stand-alone system or as integrated platform in combination with scaffolds for the delivery of ASOs for a wide range of applications in drug delivery and regenerative medicine.

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ER -

Nano-ghosts: Novel biomimetic nano-vesicles for the delivery of antisense oligonucleotides

Abstract

Bibliographical note

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