Enhanced Biofilm Infiltration by Drug‐laden Coacervate for Treating Refractory Infections

ABSTRACT The effective treatments of biofilm‐related refractory infections such as osteomyelitis are hampered by the limited drug coverage to large infected areas and infiltration into the biofilm at infection sites. Herein, guided by the hypothesis that liquid water‐immiscible coacervates with ultra‐low interfacial tension could effectively infiltrate these barriers, it is systematically screened 7 representative coacervates for their biofilm infiltration performance. Coacervates with ultra‐low interfacial tension (<0.5 mN m ^{− 1} ) showed markedly enhanced biofilm infiltration, whereas a high‐interfacial‐tension control (Gel‐Nap coacervate) and aqueous controls failed to infiltrate biofilms. However, electrostatically assembled complex coacervates suffered from poor physiological stability and cytotoxicity. The physiologically stable and biocompatible PEG‐alkyl coacervate is selected as a lead candidate for in vivo validation. In murine and canine osteomyelitis models, the selected drug‐loaded PEG‐alkyl coacervate system further demonstrated robust infiltration of microporous bone and dense biofilm, sustained local drug retention, effective eradication of Staphylococcus aureus , suppression of inflammatory cytokines, and accelerated bone regeneration. This study establishes low‐interfacial‐tension–driven infiltration as a generalizable principle for designing stable and biocompatible fluidic coacervate carriers to eradicate refractory biofilm infections.