Multifunctional pH-responsive nanocarrier for targeted azithromycin delivery and immune modulation in bacterial sepsis

Antibiotic resistance, bacterial biofilms, and resulting dysregulated immune responses pose major challenges in the management of bacterial infections, often leading to severe complications such as sepsis. This study introduces a multifunctional, pH-responsive nanocarrier based on self-assembled micelles composed of poly(ethylene glycol)-poly(β-amino ester) (PEG-PAE) and the antibiotic azithromycin (Azi). The prepared Azi-PEG-PAE micelles exhibited a negative charge under physiological conditions, which converted to positive charge in acidic environments. In acidic biofilm environments, these micelles effectively targeted negatively charged bacteria and released azithromycin, achieving enhanced biofilm eradication compared to free azithromycin. Furthermore, the micelles bound pathogen-associated molecular patterns (PAMPs), thereby mitigating excessive inflammation, reducing sepsis incidence and increasing survival in a murine peritonitis model. The desorbed PAMPs from the micelles subsequently triggered macrophages toward the M1 phenotype, further promoting bacterial clearance. This dual antibacterial and immunomodulatory strategy demonstrates a promising approach to overcome the challenges of antibiotic-resistant infections and immune dysregulation in sepsis. Severe bacterial infections and dysregulated immune responses trigger sepsis. We introduce a multifunctional, pH-responsive micellar system that enhances azithromycin delivery within acidic biofilm environments while concurrently binding pathogen-associated molecular patterns (PAMPs). By integrating targeted antimicrobial activity with immunomodulation, these micelles significantly reduce sepsis incidence and improve survival in a murine peritonitis model, offering a promising therapeutic strategy for treating bacterial sepsis.