Harnessing mRNA Vaccine Technology for Precision Antimicrobial Delivery

ABSTRACT The rise of antimicrobial resistance (AMR) presents an urgent global health crisis, projected to surpass cancer as the second leading cause of death by 2050. Existing antibiotics are becoming increasingly ineffective due to overuse, incomplete regimens, and insufficient pharmaceutical innovation. Endolysins are bacteriophage-derived enzymes that effectively lyse bacterial cell walls, offering a targeted, alternative to traditional antibiotics that do not readily elicit microbial resistance. Unlike broad-spectrum antibiotics, endolysins have precise host specificities and can clear bacterial biofilms rapidly. However, their delivery remains challenging. The use of an mRNA-based delivery systems offers significant advantages over direct protein-based therapies, including cost-effective production, scalability, and sustained protein expression for over a week. This innovative approach holds potential to revolutionize antimicrobial therapeutics by delivering high-efficacy treatments at low cost, mitigating AMR, and opening new avenues for commercial and clinical applications. Our project seeks to establish a novel antimicrobial approach that combines endolysin proteins from our metagenomic database with self-replicating mRNA (repRNA) delivery using lipid nanoparticles. This Phase I proof-of-concept study focuses on two key objectives. First, we aim to evaluate whether repRNA can successfully express a lysin which targets vancomycin-resistant Enterococcus faecium (VRE), a CDC- identified high-priority pathogen. Second, we will assess whether this lysin produced in human cells via repRNA maintains bacteriolytic activity. Our proprietary library of over two million phage-host genome connections uniquely positions us to select potent lysin candidates for further clinical development. By demonstrating the feasibility of mRNA-based lysin delivery, this project lays the groundwork for rapid commercialization and broad clinical adoption, addressing an urgent medical need. Success will accelerate the development of next-generation antimicrobials, ensuring a more sustainable and cost-effective response to AMR.