Virus-Inspired mRNA Delivery Vehicle Enabled by a Multilayered Nucleic Acid Nanocapsule

The chemical instability of mRNA complicates its future clinical application, including issues surrounding its storage, handling, and potential for delivery to patients. Herein, we describe a chemical formulation, inspired by the dynamic multidimensional structure of a virus, with the potential to address many mRNA delivery limitations by enhancing stability, effective cytosolic delivery, and enabling the ability to target mRNA expression to a specific cell receptor. It consists of a liposomal core, stabilized by a metal organic framework, encapsulated within our nucleic acid nanocapsule formulation, ultimately imparting an enzymatic trigger to gate mRNA release and expression in cells, much as a virus is degraded by proteolytic enzymes under acidic conditions in the endosome to release its genetic cargo. We refer to this formulation as a liposomal metal organic framework-nucleic acid nanocapsule, wherein we show how a multilayered delivery carrier can use both pH and enzyme-specific triggers to gate efficient mRNA delivery to the cytosol of cells in vitro, as well as in vivo. Our system can achieve sustained expression from mRNA when stored at room temperature (∼14 days), mRNA structural integrity after >100 days at -20 °C, and therapeutic efficacy in an avian influenza in vitro model. In vivo, we show the expression of therapeutically relevant proteins and changes in the distribution of fluorescent proteins within a tumor microenvironment, observing more homogeneous expression using aptamers. This work provides an approach to mRNA delivery, which extends its shelf life while providing a route to receptor-specific delivery.