Enzymatic Cellular Nanoparticles Deliver Payloads across Mucosal Barriers

Patient preferred routes of administration for therapeutics and prophylactics, such as via oral delivery and inhalation, require penetration through mucosal barriers to achieve effective bioavailability. The mucus layer is composed of glycosylated mucin proteins and serves as a robust natural defense against pathogens but also significantly impedes the delivery of medicinal agents. To overcome this barrier, we developed an innovative virus-mimicking enzymatic cellular nanoparticle designed to enhance mucopenetration. Inspired by the influenza A virus, we genetically engineered the neuraminidase protein onto the surface of mammalian cell membrane, which was subsequently used to coat mRNA-loaded lipid nanoparticle cores. This enabled the resulting nanoparticles to cleave sialic acid residues within the mucus matrix, thereby facilitating mucopenetration. In vitro studies demonstrated that these enzyme-coated cellular nanoparticles effectively traversed an artificial mucus layer, significantly enhancing mRNA delivery to underlying epithelial cells. Furthermore, in vivo experiments in a murine model showed improved lung expression of the mRNA payload after intratracheal administration. By harnessing the power of viral biomimicry, this work unveils exciting possibilities for overcoming mucosal barriers.