Harnessing DNA Tetrahedral Nanoparticles: A Novel Strategy for Co- delivery of OTUD6B siRNA and DOX Against TNBC Growth and Progression

Abstract Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking specific targeted therapeutic options. The deubiquitinizing enzyme OTUD6B is emerging as a potential player in TNBC progression. Objective The study aimed to ascertain the role of OTUD6B in TNBC progression and to exploit its therapeutic potential using a novel delivery system. Methods OTUD6B expression in TNBC was studied in relation to patient survival outcomes. We explored the potential of OTUD6B siRNA for TNBC treatment and its combined delivery with the chemotherapeutic agent, DOX, using a synthesized DNA tetrahedral nanoparticle (Td). The uptake and efficacy of the siOTUD6B/DOX@Td combination in TNBC cells were then evaluated, alongside an investigation into the underlying molecular mechanisms. Results There was a significant upregulation of OTUD6B in TNBC, inversely correlated with patient survival. The siOTUD6B/DOX@Td composite demonstrated efficient cellular uptake by TNBC cells, leading to the gene silencing of OTUD6B and controlled DOX release. This dual treatment approach enhanced apoptosis rates, increased DOX sensitivity, and inhibited TNBC cell growth, migration, and metastasis. In vivo results further confirmed the inhibition of tumor growth and metastasis without harming primary organs. Mechanistically, OTUD6B influenced TNBC progression through MDM2 stabilization and FOXO3 degradation. Conclusion Our findings highlight the pivotal role of OTUD6B in TNBC progression and underscore the potential of DNA tetrahedral nanoparticles as drug delivery systems. The combined siOTUD6B/DOX@Td strategy offers a promising therapeutic approach for TNBC and demonstrates the broader applicability of DNA nanotechnology in biomedicine.