EV-LYSG101: Extracellular Vesicles Loaded With Lysin LYSG101 for Potent Anti-Staphylococcal Activity

Biofilm-associated staphylococcal infections remain exceptionally difficult to treat due to the presence of resilient staphylococcal biofilms and the limited effectiveness of currently available antibiotics. To combat persistent infections, providers are often forced to use prolonged courses of combination antimicrobial therapies that have significant toxicities with limited effectiveness, leading to increased hospital stays, substantial health care costs and a rise in patient morbidity and mortality. Staphylococcus aureus is a dominant cause of recalcitrant biofilms, for which novel non-antibiotic therapeutics are critically needed. Lysins, a class of protein-based antimicrobials, rapidly kill staphylococci, exhibit potent anti-biofilm activity, have a low propensity of resistance development and synergy with antibiotics. To address this unmet need, we evaluate an extracellular vesicle (EV)-based delivery platform for the engineered anti-staphylococcal lysin LYSG101, designed to improve stability and localization at sites of infection. Initial proof-of-concept work is provided here, demonstrating that human serum-derived EVs can be loaded with LYSG101 to exert a potent in vitro antimicrobial effect against both planktonic and biofilm forms of S. aureus. EV-mediated delivery achieved activity equivalent to free lysin, with additional translational advantages including stability and the potential for sustained intra-articular retention. This work supports further development of the EV-mediated lysin delivery as a broadly applicable antimicrobial platform, with potential future applications in biofilm-associated infections, including prosthetic joint infection (PJI).