Reversible Disorder-to-Order Transition of Coacervates for Tumor Microenvironment-Responsive Intracellular Drug...

Area of Science:

• Biomaterials Science
• Nanotechnology
• Drug Delivery Systems

Background:

• Biological condensates formed via liquid-liquid phase separation (LLPS) show promise for intracellular drug delivery.
• Metastability of LLPS condensates limits precise phase control for responsive drug release.
• The tumor microenvironment (TME) presents unique challenges for effective drug delivery.

Purpose of the Study:

• To engineer peptide coacervates with thermoreversible transitions for controlled intracellular drug delivery.
• To develop a system for on-demand drug release triggered by TME-specific conditions.
• To enhance the stability and responsiveness of droplet-based delivery vehicles.

Main Methods:

• Incorporation of low-complexity aromatic-rich kinked segments (LARKS) as phase modulators in peptide coacervates.
• Loading of small molecules (e.g., Nile Red, FITC, Rhodamine B) to induce liquid-crystalline shells at 37 °C.
• Utilizing elevated acidity and glutathione (GSH) in the TME to trigger coacervate dissolution.
• Demonstrating intracellular delivery and ferroptosis induction using erastin-loaded coacervates in malignant melanoma cells via caveolin-mediated endocytosis.

Main Results:

• Engineered peptide coacervates exhibit thermoreversible disorder-to-order transitions.
• Loading small molecules enhanced coacervate thermostability via liquid-crystalline shell formation.
• TME conditions (acidity, GSH) triggered coacervate dissolution for on-demand drug release.
• Erastin-loaded coacervates showed enhanced ferroptosis induction in melanoma cells compared to free erastin.

Conclusions:

• Developed a gel-free, droplet-based delivery system leveraging reversible disorder-to-order transitions.
• The system enables TME-responsive intracellular drug delivery with enhanced therapeutic outcomes.
• This approach offers a promising strategy for targeted cancer therapy.