Reducible Polyethylenimine Nanoparticles for Efficient siRNA Delivery in Corneal Neovascularization Therapy

Area of Science:

• Biomedical Engineering
• Ophthalmology
• Nanotechnology

Background:

• Corneal neovascularization (CNV) poses a significant challenge in ophthalmic therapy.
• Current small interfering RNA (siRNA) treatments for CNV are limited by severe cytotoxicity from repeated drug administration.
• Developing safe and effective ocular delivery systems for siRNA is crucial for advancing CNV therapy.

Purpose of the Study:

• To establish a safe and effective ocular delivery system for therapeutic small interfering RNA (siRNA) in corneal neovascularization (CNV) therapy.
• To overcome the cytotoxicity hurdle associated with conventional siRNA treatments for CNV.
• To develop and validate a novel reducible branched polyethylenimine (rBPEI)-based nanoparticle (NP) system for siRNA delivery.

Main Methods:

• Synthesis of reducible branched polyethylenimine (rBPEI) via thiolation and self-crosslinking of branched polyethylenimine (BPEI).
• Formation of stable siRNA/rBPEI nanoparticles (siRNA-rBPEI-NPs) using the synthesized rBPEI.
• In vivo assessment of siRNA release and distribution in the corneal region of Sprague Dawley rats following subconjunctival injection of fluorescent-labeled siRNA-rBPEI-NPs.

Main Results:

• Successfully synthesized high molecular weight rBPEI through self-crosslinking under mild conditions.
• Created stable siRNA-rBPEI-NPs capable of encapsulating and protecting siRNA.
• Demonstrated effective degradation of the rBPEI matrix in the reductive cytosol, leading to rapid siRNA release.
• Confirmed siRNA distribution throughout the corneal region after subconjunctival injection in rats, validating the system's proof of concept.

Conclusions:

• The developed siRNA-rBPEI-NP system offers a promising strategy for safe and effective ocular siRNA delivery in CNV therapy.
• The rBPEI-based nanoparticles effectively protect siRNA and release it in the target corneal tissue, mitigating cytotoxicity concerns.
• This novel delivery system represents a significant advancement in the potential treatment of corneal neovascularization.