"Clickable" ZIF-8 for Cell-Type-Specific Delivery of Functional Proteins

Area of Science:

• Biotechnology
• Nanomedicine
• Molecular Biology

Background:

• Protein therapy offers advantages over small molecules for targeting difficult cellular sites.
• Selective intracellular protein delivery remains a significant challenge in therapeutic development.

Purpose of the Study:

• To develop a robust and selective strategy for intracellular protein delivery.
• To demonstrate the utility of this system for delivering functional proteins and gene editing tools to specific cell types.

Main Methods:

• Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles were synthesized, encapsulating proteins and doped with norbornene-modified imidazole (MIM-Nor).
• Nanoparticles were functionalized with cetuximab (Cet) via click chemistry for targeted delivery.
• The system, Cet@protein@ZIF-8N, was tested for delivering RNase A and a Cas9/sgRNA complex.

Main Results:

• Cet@RNase A@ZIF-8N nanoparticles selectively delivered functional RNase A to epidermal growth factor receptor (EGFR)-overexpressing cells.
• The system demonstrated effective cell-type-specific gene editing by delivering a Cas9/sgRNA complex to knockdown glutathione peroxidase (GPX4).
• In vitro and in vivo experiments confirmed the efficacy and selectivity of the delivery system.

Conclusions:

• A novel nanoparticle-based platform enables targeted intracellular delivery of proteins and gene editing components.
• This strategy holds significant potential for advancing cancer therapy and precision medicine applications.