DNA tetrahedral nanoparticles: Co-delivery of siOTUD6B/DOX against triple-negative breast cancer

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. • We examined the role and mechanisms of OTUD6B in triple-negative breast cancer. • We developed nanoparticles loaded with DOX and siOTUD6B (siOTUD6B/DOX@Td). • OTUD6B is upregulated in breast cancer and is associated with low survival. • OTUD6B promotes TNBC growth or metastasis by stabilizing MDM2 and inhibiting intracellular accumulation of FOXO3a. • siOTUD6B/DOX@Td exerts a synergistic inhibitory effect on TNBC cells' growth, invasion, and migration.