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

Area of Science:

• Oncology
• Nanotechnology
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted therapies.
• Ovarian tumor domain-containing 6B (OTUD6B) is implicated in TNBC progression.
• Targeting OTUD6B presents a potential therapeutic avenue for TNBC.

Purpose of the Study:

• To investigate the role of OTUD6B in TNBC.
• To evaluate the therapeutic efficacy of co-delivering siOTUD6B and doxorubicin (DOX) using DNA nanoparticles (Tds) in TNBC models.
• To elucidate the molecular mechanisms underlying OTUD6B's function in TNBC.

Main Methods:

• In vitro and xenograft models of TNBC were utilized.
• Tetrahedral DNA nanoparticles (Tds) were synthesized for co-delivery of siOTUD6B and DOX.
• Cellular uptake, OTUD6B knockdown, DOX release, apoptosis, cell growth, migration, and metastasis were assessed.
• In vivo tumor growth and organ damage were evaluated.
• Mechanistic studies focused on MDM2 and FOXO3a interactions with OTUD6B.

Main Results:

• siOTUD6B/DOX@Td nanoparticles showed efficient cellular uptake and controlled DOX release in TNBC cells.
• Treatment enhanced apoptosis, increased DOX sensitivity, and inhibited TNBC cell growth, migration, and metastasis.
• In vivo studies demonstrated significant inhibition of tumor growth and metastasis without primary organ damage.
• OTUD6B was found to stabilize MDM2 and degrade FOXO3a, promoting TNBC progression.

Conclusions:

• DNA nanoparticles loaded with siOTUD6B and DOX are effective in treating TNBC.
• This combined therapeutic approach offers a potential strategy for managing aggressive TNBC.
• Targeting the OTUD6B/MDM2/FOXO3a axis presents a novel therapeutic mechanism for TNBC.