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

Protein therapy provides a powerful alternative to small-molecule-based therapy, especially on cellular targets that are normally considered to be less druggable. Intracellular protein delivery, in particular, in a cell-type-specific manner, is still highly challenging. At present, few general strategies are available for the robust and selective intracellular delivery of proteins. In this Letter, by using zeolitic imidazolate framework-8 (ZIF-8) as protein-encapsulated nanoparticles and simultaneous doping with norbornene-modified imidazole (MIM-Nor), followed by surface attachment of the resulting nanoparticles with cetuximab (Cet) through click chemistry, we successfully synthesized Cet@protein@ZIF-8N, which was subsequently used for the selective intracellular delivery of functional proteins to epidermal-growth-factor-receptor (EGFR)-overexpressed cells. Both in-cell and in vivo experiments proved that Cet@RNase A@ZIF-8N can effectively deliver RNase A with the retention of selective inhibition. Furthermore, the same strategy was successfully applied to cell-type-specific gene editing through the delivery of a Cas9/sgRNA complex to knockdown the endogenous expression of glutathione peroxidase (GPX4), a key protein in ferroptosis. Our new system thus has potential implications in future cancer treatment and the development of precision medicine.