Polymersome‐Enabled Multimodal Delivery of Tobramycin and Doripenem for Targeted Eradication of Pseudomonas aeruginosa Biofilms in Chronic Rhinosinusitis

Biofilms formed by Pseudomonas aeruginosa pose a major therapeutic challenge due to limited antibiotic penetration and increased tolerance. Here, we present a polymersome-based platform designed to enable biofilm penetration and controlled antibiotic release. pH-responsive polymersomes (∼100 nm, PEG-p(CL-g-TMCimid.)) were prepared by incorporating imidazole groups into the hydrophobic block of an amphiphilic copolymer, allowing rapid disassembly and tobramycin (TOB) release under mildly acidic conditions characteristic of the biofilm microenvironment. In parallel, inert PEG-p(CL-g-TMC) polymersomes were used to achieve sustained release of doripenem (DOR). Quartz crystal microbalance with dissipation (QCM-D) monitoring demonstrated reversible interactions between polymersomes and alginate, a key component of the biofilm matrix, supporting their ability to penetrate the extracellular polymeric substance (EPS). All polymersome formulations were well tolerated by nasal epithelial cells. Antibiofilm efficacy was evaluated against mature P. aeruginosa biofilms under flow conditions. pH-responsive blank polymersomes exhibited pronounced intrinsic antibiofilm activity, exceeding that of antibiotic-loaded monotherapies and bolus antibiotic administration. Notably, co-dosing with pH-responsive polymersomes and DOR-loaded inert polymersomes resulted in the most effective biofilm eradication. Overall, the results demonstrate that the pH-responsive polymersome carrier contributes substantially to antibiofilm activity, while sustained DOR delivery may further enhance therapeutic efficacy against biofilm-associated infections.