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Nano Research 2023, 16(12): 13309-13321 https://doi.org/10.1007/s12274-023-6105-0
Research Article | Issue | Published: 13 October 2023

Dual-functional extracellular vesicles enable synergistic treatment via m6A reader YTHDF1-targeting epigenetic regulation and chemotherapy

Show Author's Information Rong Du1,2,  Qing You1,  Jingyi Liu1,2,  Chen Wang1,2( ),  Ling Zhu1,2( ),  Yanlian Yang1,2( )
CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China
University of Chinese Academy of Sciences, Beijing 100049, China
Keywords:
small interfering RNA (siRNA) delivery, ovarian cancer, extracellular vesicles, docetaxel, N6-methyladenosine (m6A) modulators
Topics:
Nano biology
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Du R, You Q, Liu J, et al. Dual-functional extracellular vesicles enable synergistic treatment via m6A reader YTHDF1-targeting epigenetic regulation and chemotherapy. Nano Research, 2023, 16(12): 13309-13321. https://doi.org/10.1007/s12274-023-6105-0
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Abstract Full text Electronic supplementary material About this article

Chemotherapy remains one of the most prevailing strategies for cancer treatment. However, its treatment effect is hampered by drug resistance, nonspecific tumor targeting, and severe toxic side effects. Combination chemotherapy with synergistic effect has become an attractive tumor therapy. N6-methyladenosine (m6A) regulators determine the fate of m6A-modified transcripts and play vital roles in cancer development and drug resistance. Gene therapy such as small interfering RNA (siRNA) is a promising strategy to reduce the abnormal gene expression of m6A regulators. However, its poor selectivity and high systemic toxicity necessitate the use of delivery vectors to target specific cells and tissues. Here, we constructed a dual-functional targeted nanodrug platform for the synergetic m6A-associated epigenetic regulation and chemotherapy of ovarian cancer. We encapsulated siRNA targeting the m6A reader YT521-B homology (YTH) N6-methyladenosine RNA-binding protein 1 (YTHDF1) and docetaxel (DTX), the first-line chemotherapeutic agent of ovarian cancer, into mesenchymal stem cell-derived small extracellular vesicles (MsEVs). This nanosystem exhibits significant tumor targeting and endo/lysosomal escape of siYTHDF1. It effectively depletes YTHDF1 and suppresses the protein translation of eukaryotic translation initiation factor 3 subunit C (EIF3C) in an m6A-dependent manner. The combination of YTHDF1-targeting epigenetic regulation significantly enhances the anti-tumor effect of DTX and effectively inhibits ovarian cancer progression without causing significant systemic toxicity. This co-delivery nanoplatform offers a promising approach for combinational cancer treatment, showing improved anti-tumor efficacy through the synergistic effects of epigenetic regulation and chemotherapeutic inhibition.


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Electronic supplementary material
About this article

Dual-functional extracellular vesicles enable synergistic treatment via m6A reader YTHDF1-targeting epigenetic regulation and chemotherapy

Show Author's information Rong Du1,2, Qing You1, Jingyi Liu1,2, Chen Wang1,2( ), Ling Zhu1,2( ), Yanlian Yang1,2( )
CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China
University of Chinese Academy of Sciences, Beijing 100049, China

Abstract

Chemotherapy remains one of the most prevailing strategies for cancer treatment. However, its treatment effect is hampered by drug resistance, nonspecific tumor targeting, and severe toxic side effects. Combination chemotherapy with synergistic effect has become an attractive tumor therapy. N6-methyladenosine (m6A) regulators determine the fate of m6A-modified transcripts and play vital roles in cancer development and drug resistance. Gene therapy such as small interfering RNA (siRNA) is a promising strategy to reduce the abnormal gene expression of m6A regulators. However, its poor selectivity and high systemic toxicity necessitate the use of delivery vectors to target specific cells and tissues. Here, we constructed a dual-functional targeted nanodrug platform for the synergetic m6A-associated epigenetic regulation and chemotherapy of ovarian cancer. We encapsulated siRNA targeting the m6A reader YT521-B homology (YTH) N6-methyladenosine RNA-binding protein 1 (YTHDF1) and docetaxel (DTX), the first-line chemotherapeutic agent of ovarian cancer, into mesenchymal stem cell-derived small extracellular vesicles (MsEVs). This nanosystem exhibits significant tumor targeting and endo/lysosomal escape of siYTHDF1. It effectively depletes YTHDF1 and suppresses the protein translation of eukaryotic translation initiation factor 3 subunit C (EIF3C) in an m6A-dependent manner. The combination of YTHDF1-targeting epigenetic regulation significantly enhances the anti-tumor effect of DTX and effectively inhibits ovarian cancer progression without causing significant systemic toxicity. This co-delivery nanoplatform offers a promising approach for combinational cancer treatment, showing improved anti-tumor efficacy through the synergistic effects of epigenetic regulation and chemotherapeutic inhibition.

Keywords: small interfering RNA (siRNA) delivery, ovarian cancer, extracellular vesicles, docetaxel, N6-methyladenosine (m6A) modulators

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Publication history
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Acknowledgements

Publication history

Received: 03 April 2023
Revised: 09 August 2023
Accepted: 17 August 2023
Published: 13 October 2023
Issue date: December 2023

Copyright

© Tsinghua University Press 2023

Acknowledgements

Acknowledgements

This study was supported by the Strategic Priority Research Program of Chinese Academy of Sciences (No. XDB36000000), the National Key Research and Development Program of China (No. 2021YFA1201504), and the National Natural Science Foundation of China (Nos. 21721002 and 31971295). The animal study protocol was approved by the Ethics Committee of the National Center for Nanoscience and Technology of China.

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