Transferrin-Appended Nanocaplet for Transcellular siRNA Delivery into Deep Tissues

Area of Science:

• Biotechnology
• Nanomedicine
• Molecular Biology

Background:

• Transferrin (Tf) facilitates transcytosis, a process involving endocytosis and exocytosis.
• Efficient delivery of small interfering RNA (siRNA) to deep tissues remains a challenge for RNA interference (RNAi) therapies.

Purpose of the Study:

• To develop a transferrin-appended nanocaplet (TfNC⊃siRNA) for deep tissue delivery of siRNA.
• To achieve effective RNA interference (RNAi) in deep tissue environments.

Main Methods:

• A novel macromonomer (AzGu) with guanidinium, azide, and protected thiol groups was synthesized.
• siRNA was complexed with AzGu, followed by oxidative polymerization to form AzNC⊃siRNA.
• Click chemistry and photochemical reactions were used to functionalize the nanocaplet with bioadhesive dendrons, benzophenone, and transferrin.

Main Results:

• The smallest siRNA-containing reactive nanocaplet reported to date was created.
• The transferrin-appended nanocaplet (TfNC⊃siRNA) demonstrated deep tissue penetration, reaching up to nearly 70 μm into cancer spheroids.
• Tf-induced transcytosis was identified as the mechanism for deep tissue permeation.

Conclusions:

• The developed TfNC⊃siRNA system is a promising platform for deep tissue delivery of therapeutic RNA.
• This nanocaplet technology overcomes previous limitations in achieving significant penetration depth for RNAi applications.
• The study highlights the potential of transferrin-mediated transcytosis for enhancing drug delivery in complex 3D tissue models.