In vivo self-assembled small RNA targets H19 lncRNA for the treatment of colorectal cancer

作者：Ying Sun, Yixuan Zhao, Xue Ni, Yixuan Yang, Zheng Fu, Rui Liu, Chen‐Yu Zhang, Xi Chen · 发表于：Journal of Controlled Release · 年份：2023 · DOI：10.1016/j.jconrel.2023.04.026 · 被引用次数：21 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、Extracellular vesicles in disease

The majority of molecularly targeted therapies in clinical use target disease-related proteins, but only a small fraction (∼1.5%) of human genome is protein-coding region. Considering that ∼70% of human genome is transcribed to noncoding RNAs, targeting noncoding RNAs rather than protein-coding RNAs can significantly expand the proportion of human genome that can be manipulated. H19 long noncoding RNA (lncRNA) is aberrantly expressed in a variety of cancer types and actively contributes to multiple steps of tumorigenesis. Therefore, we selected H19 as a representative target and designed synthetic anti-H19 construct for the self-assembly and delivery of anti-H19 small RNA (sRNA) to prevent colorectal cancer development and metastasis based on the natural ability of the host liver to package sRNA-encapsulating small extracellular vesicles (sEVs) and the endogenous circulating sEVs to transfer sRNA. As anticipated, the synthetic anti-H19 construct successfully generated anti-H19 sRNA-encapsulating sEVs and exhibited high silencing efficiency on H19 lncRNA in an ex vivo model. In orthotopic and lung metastasis mouse models of colorectal cancer, the anti-H19 construct exhibited significantly superior therapeutic efficacy over 5-fluorouracil (5-Fu) in preventing primary tumor growth and lung metastasis. Particularly, the anti-H19 sRNA-encapsulating sEVs were generated in a nontoxic, nonimmunogenic and biocompatible manner. In summary, this study demonstrates that the in vivo self-...