Nanoscale ATP-Responsive Zeolitic Imidazole Framework-90 as a General Platform for Cytosolic Protein Delivery and...

Metal-organic frameworks (MOFs) are an emerging class of nanocarriers for drug delivery, owing to their tunable chemical functionality. Here we report ATP-responsive zeolitic imidazole framework-90 (ZIF-90) as a general platform for cytosolic protein delivery and CRISPR/Cas9 genome editing. The self-assembly of imidazole-2-carboxaldehyde and Zn²⁺ with protein forms ZIF-90/protein nanoparticles and efficiently encapsulates protein. It was found that, in the presence of ATP, the ZIF-90/protein nanoparticles are degraded to release protein due to the competitive coordination between ATP and the Zn²⁺ of ZIF-90. Intracellular delivery studies showed that the ZIF-90/protein nanoparticle can deliver a large variety of proteins into the cytosol, regardless of protein size and molecular weight. The delivery of cytotoxic RNase A efficiently prohibits tumor cell growth, while the effective delivery of genome-editing protein Cas9 knocks out the green fluorescent protein (GFP) expression of HeLa cells with efficiency up to 35%. Given the fact that ATP is upregulated in disease cells, it is envisaged that the ATP-responsive protein delivery will open up new opportunities for an advanced protein delivery and CRISPR/Cas9 genome editing for targeted disease treatment.