Cui Zhifen, Huang Furong, Fang Kun, Yan Jingyue, Zhang Yuebao, Kang Diana D, Zhou Yufan, Zhao Yue, Everitt Jeffrey I, Hankey William, Armstrong Andrew J, Huang Jiaoti, Wang Hongyan, Jin Victor X, Dong Yizhou, Wang Qianben
Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.
Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
Adv Sci (Weinh). 2025 Jun;12(23):e2417605. doi: 10.1002/advs.202417605. Epub 2025 May 11.
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.
转移性癌症是癌症死亡的主要原因，常常表现出对某些转录因子（TFs）的高度依赖，这些转录因子是致癌信号的主要调节因子，但通常无法被小分子靶向。开发了选择性器官内细胞靶向（SCORT）纳米颗粒，用于在体内将CRISPR/Cas13d mRNA和gRNA精确递送至转移性癌细胞，旨在敲低不可成药的致癌转录因子HoxB13。在由HoxB13驱动的前列腺癌肝转移模型中，重复进行全身SCORT-Cas13d-gHoxB13治疗可显著降低HoxB13表达、减少转移并延长小鼠生存期。长期治疗对主要器官功能、组织学或免疫标志物无显著影响。从机制上讲，SCORT-Cas13d-gHoxB13治疗通过调节多个基因通路抑制转移性肿瘤增殖和血管生成，同时促进细胞凋亡。出乎意料的是，它抑制了Snail的非经典、不依赖上皮-间质转化（EMT）的致癌功能。这些发现表明，SCORT-Cas13d-gHoxB13可以有效且安全地靶向转移性前列腺癌中不可成药的HoxB13，将CRISPR/Cas13d定位为一种潜在的治疗方法。
