Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options. Recently, the deubiquitinizing enzyme ovarian tumor domain-containing 6B (OTUD6B) has been reported to play a potential role in TNBC progression. Therefore, this study investigates the role and underlying molecular mechanisms of OTUD6B in vitro and xenograft models of TNBC. Specifically, we examined the therapeutic effects of siOTUD6B and doxorubicin (DOX) co-delivery using synthesized tetrahedral DNA nanoparticles (Tds) on tumor growth and progression. Additionally, the uptake and efficacy of the siOTUD6B/DOX@Td in TNBC cells were evaluated. Notably, the siOTUD6B/DOX@Td nanoparticle demonstrated efficient cellular uptake by TNBC cells, resulting in OTUD6B knockdown and controlled release of DOX. Additionally, siOTUD6B/DOX@Td treatment enhanced apoptosis rates increased DOX sensitivity, and inhibited TNBC cell growth, migration, and metastasis. Moreover, in vivo experiments confirmed that siOTUD6B/DOX@Td treatment inhibited tumor growth and metastasis without damaging the primary organs. Mechanistically, OTUD6B regulates TNBC progression by stabilizing murine double minute 2 (MDM2) and degrading forkhead box O3a (FOXO3a). Conclusively, this study demonstrates the potential applicability of DNA nanoparticles loaded with DOX and siOTUD6B for TNBC treatment.

中文翻译：

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DNA 四面体纳米颗粒：siOTUD6B/DOX 的共同递送对抗三阴性乳腺癌


三阴性乳腺癌 （TNBC） 是乳腺癌的一种侵袭性亚型，靶向治疗选择有限。最近，据报道，含有去泛素化酶卵巢肿瘤结构域的 6B （OTUD6B） 在 TNBC 进展中起潜在作用。因此，本研究探讨了 OTUD6B 在 TNBC 的体外和异种移植模型中的作用和潜在的分子机制。具体来说，我们检查了使用合成的四面体 DNA 纳米颗粒 （Tds） 共同递送 siOTUD6B 和多柔比星 （DOX） 对肿瘤生长和进展的治疗效果。此外，还评估了 siOTUD6B/DOX@Td 在 TNBC 细胞中的摄取和疗效。值得注意的是，siOTUD6B/DOX@Td 纳米颗粒表现出 TNBC 细胞的有效细胞摄取，导致 OTUD6B 敲低和 DOX 的受控释放。此外，siOTUD6B/DOX@Td 治疗提高了细胞凋亡率，增加了 DOX 敏感性，并抑制了 TNBC 细胞的生长、迁移和转移。此外，体内实验证实 siOTUD6B/DOX@Td 治疗可抑制肿瘤生长和转移，而不会损害原代器官。从机制上讲，OTUD6B 通过稳定小鼠双分 2 （MDM2） 和降解叉头盒 O3a （FOXO3a） 来调节 TNBC 进展。总之，本研究证明了负载 DOX 和 siOTUD6B 的 DNA 纳米颗粒对 TNBC 治疗的潜在适用性。