Metal-organic frameworks for simultaneous gene and small molecule delivery in vitro and in vivo

•Metal-organic frameworks for co-delivery of a transgene and a drug-like molecule are designed for the first time.•The first successful metal-organic frameworks based in vivo delivery of a functional gene is presented.•The developed nanocarrier has high loading capacity for both payloads. Nanoparticles based on metal–organic frameworks (nMOF) became one of the most promising class of drug delivery vehicles due to their ability to transport a great range of payloads, high capacity, tunable release, and the potential to simultaneously transport several different payloads to achieve synergistic therapeutic effect. However, despite the significant progress with small molecule payloads (including siRNA), delivery of functional genes has been greatly limited. Here, we show the first nanoscale modified MOFs (modMOF) that allow: i)co-delivery of a transgene and a drug-like molecule; ii) in vivo gene delivery and expression. The multimodal modMOFs are fabricated via growing of the metal–organic framework shell on top of the magnetic core and then surface-modified with multiple polymers that do not inhibit incorporation of the small-molecule payload inside the particle and allow further binding of the plasmid DNA. Such structure allows efficient transfection by the plasmid DNA of virtually any size while fully retaining the superior small-molecule transport capacity of the MOF shell. The magnetic core offers additional functionality to the agent including capability for the highly accurate tracking in vivo. Performance of the agents is demonstrated in vitro for different cell lines and in vivo upon intravenous injection of the agents in mice. Expression of the target protein in lungs supplemented with the slow diffuse release of the small molecule payload suggests that the developed modMOF synthesis strategy may offer novel routes for lung disease treatment based on co-targeting of multiple signaling pathways.