Proteolysis Targeting Chimera Loaded Extracellular Vesicles for Developing Triple Negative Breast Cancer Treatment.

Area of Science:

• Oncology
• Nanotechnology
• Biotechnology

Background:

• Proteolysis targeting chimeras (PROTACs) are a promising cancer therapy but face challenges with in vivo delivery and stability.
• Triple-negative breast cancer (TNBC) requires effective targeted therapies due to its aggressive nature.

Purpose of the Study:

• To enhance the in vivo therapeutic efficacy of PROTACs by utilizing extracellular vesicles (EVs) for delivery.
• To develop a scalable method for loading PROTACs into EVs for improved cancer treatment.

Main Methods:

• A novel microfluidic droplet-based EV electro-transfection system (μDES) was employed for efficient PROTAC loading into EVs.
• The YX968 PROTAC, targeting HDAC3 and HDAC8, was loaded into EVs using the μDES system.
• The efficacy of EV-delivered YX968 was evaluated in TNBC mouse models.

Main Results:

• The μDES system demonstrated high loading efficiency and maintained EV integrity for YX968-loaded EVs.
• EV-based delivery significantly enhanced intratumoral degradation of HDAC3 and HDAC8 in TNBC models compared to PROTAC alone.
• YX968 loaded EVs resulted in advanced TNBC tumor inhibition with no observable tissue toxicity.

Conclusions:

• EVs, loaded via the scalable μDES system, represent an effective strategy for in vivo PROTAC delivery, improving drug stability, bioavailability, and tissue penetration.
• This EV-based delivery approach addresses key limitations in PROTAC clinical translation for enhanced cancer therapy.