SCORT–Cas13d Nanotherapy Precisely Targets the ‘Undruggable’ Transcription Factor HoxB13 in Metastatic Prostate Cancer In Vivo

SCORT–Cas13d Nanotherapy Precisely Targets the ‘Undruggable’ Transcription Factor HoxB13 in Metastatic Prostate Cancer In Vivo

Abstract Metastatic cancer, the primary cause of cancer mortality, frequently exhibits heightened dependence on certain transcription factors (TFs), which serve as master regulators of oncogenic signaling yet are often untargetable by small molecules. Selective Cell in ORgan Targeting (SCORT) nanopa...

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Main Authors: Zhifen Cui, Furong Huang, Kun Fang, Jingyue Yan, Yuebao Zhang, Diana D. Kang, Yufan Zhou, Yue Zhao, Jeffrey I. Everitt, William Hankey, Andrew J Armstrong, Jiaoti Huang, Hongyan Wang, Victor X. Jin, Yizhou Dong, Qianben Wang
Format: Article
Language:English
Published: Wiley 2025-06-01
Series:Advanced Science
Subjects:
HoxB13
mechanistic insights into therapeutic action
metastatic prostate cancer
SCORT‐Cas13d nanotherapy
SCORT nanoparticles
undruggable oncogenic transcription factors
Online Access:https://doi.org/10.1002/advs.202417605
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Summary:Abstract Metastatic cancer, the primary cause of cancer mortality, frequently exhibits heightened dependence on certain transcription factors (TFs), which serve as master regulators of oncogenic signaling yet are often untargetable by small molecules. Selective Cell in ORgan Targeting (SCORT) nanoparticles are developed for precise CRISPR/Cas13d mRNA and gRNA delivery to metastatic cancer cells in vivo, aiming to knock down the undruggable oncogenic TF HoxB13. In prostate cancer liver metastasis models driven by HoxB13, repeated systemic SCORT‐Cas13d‐gHoxB13 treatment significantly decreases HoxB13 expression, reduces metastasis, and extends mouse survival. Prolonged treatment shows no significant impact on major organ function, histology or immune markers. Mechanistically, SCORT‐Cas13d‐gHoxB13 treatment suppresses metastatic tumor proliferation and angiogenesis while promoting apoptosis by regulating multiple gene pathways. Unexpectedly, it inhibits the non‐canonical, EMT‐independent oncogenic function of Snail. These findings suggest that SCORT‐Cas13d‐gHoxB13 can effectively and safely target the undruggable HoxB13 in metastatic prostate cancer, positioning CRISPR/Cas13d as a potential treatment.
ISSN:2198-3844

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