期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2112696119
关键词
KDM6A; mRNA nanoparticles; bladder cancer; intravesical delivery; elemene
资金
- National Natural Science Foundation of China [81730108, 81973635]
- Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars [LR18H160001]
- US METAvivor Early Career Investigator Award [2018A020560]
- Harvard Medical School/Brigham and Women's Hospital Department of Anesthesiology-Basic Scientist Grant [2420 BPA075]
- Khoury Innovation Award [2020A003219]
- American Heart Association Collaborative Sciences Award [2018A004190]
- Department of Anesthesiology, Perioperative and Pain Medicine
A mucoadhesive messenger RNA nanoparticle strategy was used for intravesical delivery of KDM6A-mRNA in mice with orthotopic Kdm6a-null BCa, demonstrating KDM6A's therapeutic potential in inhibiting BCa metastasis.
Lysine-specific demethylase 6A (KDM6A), also named UTX, is frequently mutated in bladder cancer (BCa). Although known as a tumor suppressor, KDM6A's therapeutic potential in the metastasis of BCa remains elusive. It also remains difficult to fulfill the effective up-regulation of KDM6A levels in bladder tumor tissues in situ to verify its potential in treating BCa metastasis. Here, we report a mucoadhesive messenger RNA (mRNA) nanoparticle (NP) strategy for the intravesical delivery of KDM6A-mRNA in mice bearing orthotopic Kdm6a-null BCa and show evidence of KDM6A's therapeutic potential in inhibiting the metastasis of BCa. Through this mucoadhesive mRNA NP strategy, the exposure of KDM6A-mRNA to the in situ BCa tumors can be greatly prolonged for effective expression, and the penetration can be also enhanced by adhering to the bladder for sustained delivery. This mRNA NP strategy is also demonstrated to be effective for combination cancer therapy with other clinically approved drugs (e.g., elemene), which could further enhance therapeutic outcomes. Our findings not only report intravesical delivery of mRNA via a mucoadhesive mRNA NP strategy but also provide the proof-of-concept for the usefulness of these mRNA NPs as tools in both mechanistic understanding and translational study of bladder-related diseases.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据