Decoy Extracellular Vesicles Overcome Triple-Negative Breast Cancer Heterogeneity via Membrane-Cytoplasm-Mitochondria...

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Triple-negative breast cancer (TNBC) presents significant heterogeneity, complicating treatment strategies.
• Cancer stem cells (CSCs) and immune checkpoint (IC) upregulation contribute to TNBC's resistance to therapies.
• Extracellular vesicles (EVs) from exhausted T cells can deliver ICs to tumor cells, including CSCs.

Purpose of the Study:

• To develop a novel extracellular vesicle (EV)-based delivery system for overcoming TNBC heterogeneity.
• To simultaneously target cancer stem cells (CSCs) and immune checkpoints (ICs) within TNBC.
• To enhance the efficacy of immunotherapy by addressing metabolic plasticity and immune escape.

Main Methods:

• Engineered a novel EV delivery system (siT/MOF@EVs) to codeliver TEAD4-siRNA (siTEAD4) and a mitochondria-targeting metal-organic framework (T/MOF).
• Utilized EVs as decoys to block IC ligands on tumor cells, particularly CSCs.
• Leveraged nanozymes within mitochondria to trigger oxidative bursts and inhibit tumor metabolism.

Main Results:

• The siT/MOF@EVs system effectively inhibited CSC growth and overcame immunotherapy resistance by delivering siTEAD4.
• Co-delivery of siTEAD4 and T/MOF synergistically blocked tumor aerobic glycolysis and oxidative phosphorylation.
• Demonstrated significant inhibition of tumor growth and metastasis, inducing immunogenic tumor cell death and protective immune memory in TNBC models without systemic toxicity.

Conclusions:

• The engineered siT/MOF@EVs system successfully overcomes TNBC heterogeneity by targeting multiple pathways.
• This novel therapeutic strategy shows potent anti-tumor activity and induces a favorable immune response.
• The findings suggest a promising new approach for treating aggressive triple-negative breast cancer.