Engineering Injectable, Adhesive, and Drug‐Free Hydrogel for Efficient Acute Otitis Media Treatment by Biofilm Disruption and Immune Modulation

Abstract Acute otitis media (AOM) is a prevalent pediatric bacterial infection that is conventionally managed with prolonged oral antibiotic regimens. However, the therapeutic efficacy of this approach is increasingly compromised by the emergence of antibiotic resistance and bacterial biofilms. This study presents a novel multifunctional hydrogel, synthesized through the cross‐linking of quaternary chitosan (QCS) with protocatechualdehyde (PA), to address these challenges. The QCS‐PA hydrogel exhibits robust antibacterial activity against Escherichia coli and Staphylococcus aureus ( S. aureus ), effectively disrupting bacterial membranes and biofilms in vitro. For the in vivo studies using S. aureus ‐induced and lipopolysaccharides (LPS)‐induced AOM animal models, the hydrogel significantly reduces bacterial burden within middle ear fluid and disrupts biofilms adhering to the middle ear mucosa. A single intratympanic administration of the hydrogel further demonstrates pronounced anti‐inflammatory and immunomodulatory effects, evidenced by the suppression of inflammatory cell infiltration, the downregulation of pro‐inflammatory cytokines levels, and the polarization of macrophages from the pro‐inflammatory M1 phenotype to the anti‐inflammatory M2 phenotype. Transcriptome analyses reveal the downregulation of key inflammatory genes and associated signaling pathways, especially interleukin 17 (IL‐17)‐mediated inflammation signaling. Collectively, these findings establish the specific QCS‐PA hydrogel as an efficient drug‐free biomaterial for AOM therapy, offering multifunctional biofilm disruption and immune modulation without reliance on conventional antibiotics.