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 <i>in vitro</i>, as well as <i>in vivo</i>. 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 <i>in vitro</i> model. <i>In vivo,</i> 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.