Protease-triggered siRNA delivery vehicles

Area of Science:

• Biotechnology
• Polymer Chemistry
• RNA Therapeutics

Background:

• * Delivering membrane-impermeable therapeutics safely to the cytoplasm is challenging.
• * Conventional methods can cause toxicity through non-specific cell membrane lysis.
• * Endogenous proteases offer a potential trigger for controlled drug release.

Purpose of the Study:

• * To develop a controlled cytoplasmic delivery mechanism for therapeutics.
• * To achieve functional delivery of small interfering RNA (siRNA) using a protease-triggered system.
• * To create masked polymer-siRNA delivery vehicles for targeted cellular uptake.

Main Methods:

• * Synthesized protease-sensitive polymer masking reagents based on polyethylene glycol (PEG).
• * Incorporated N-acetylgalactosamine for targeting hepatocytes via asialoglycoprotein receptors.
• * Formulated masked polymer-siRNA delivery vehicles with controlled size, charge, and stability.

Main Results:

• * Proteolytic hydrolysis of masked polymers restored membrane-disrupting activity upon endocytosis.
• * Functional delivery of siRNA into cells was achieved after subcutaneous administration.
• * The delivery system demonstrated potential for extrahepatic targeting with ligand modification.

Conclusions:

• * A novel, protease-triggered system enables safe and effective cytoplasmic delivery of siRNA.
• * Reversible polymer inhibition and protease-sensitive substrates allow controlled therapeutic release.
• * This platform holds promise for targeted RNA therapeutics and broader applications beyond the liver.