Abstract
Lytic bacteriophages, viruses that lyse (kill) bacteria, hold great promise for treating infections, including wound infections caused by antimicrobial-resistant Pseudomonas aeruginosa. However, the optimal dosing and delivery strategies for phage therapy remain unclear. In a mouse wound infection model, we investigated the impact of dose, frequency, and administration route on the efficacy of phage therapy. We find that topical but not intravenous delivery is effective in this model. High-doses of phage reduces bacterial burden more effectively than low-doses, and repeated dosing achieves the highest eradication rates. Building on these insights, we developed "HydroPhage", a hyaluronan-based hydrogel system that uses dynamic covalent crosslinking to deliver high-titre phages over one week. HydroPhage eradicates infections five times more effectively than intravenous injection. We conclude that hydrogel-based sustained phage delivery enhances the efficacy of phage therapy and offers a practical, well-tolerated option for topical application.