Intravesical delivery of KDM6A -mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS 2022-02, Vol.119 (7)
• Main Authors: Kong, Na, Zhang, Ruonan, Wu, Gongwei, Sui, Xinbing, Wang, Junqing, Kim, Na Yoon, Blake, Sara, De, Diba, Xie, Tian, Cao, Yihai, Tao, Wei
• Format: Article
• Language: English
• Subjects: Adhesiveness; Administration, Intravesical; Animals; Biological Sciences; Bladder; Bladder cancer; Cancer; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Genetic Therapy; Histone Demethylases - genetics; Histone Demethylases - metabolism; Histone Demethylases - pharmacology; Humans; Lysine; Medicin och hälsovetenskap; Metastases; Metastasis; Mice; Mice, Nude; mRNA; Mucous Membrane; Nanoparticles; Nanoparticles - chemistry; Neoplasm Metastasis - prevention & control; Neoplasms, Experimental - therapy; Physical Sciences; RNA, Messenger - administration & dosage; RNA, Messenger - metabolism; RNA, Messenger - pharmacology; Tumor suppressor genes; Tumors; Urinary Bladder Neoplasms
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2112696119

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 -mRNA in mice bearing orthotopic -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 -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.