Inhaled Micelle of Antimicrobial Protein-Polymer Conjugate with Less Positive Charge Leads to Better Mucus...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Infectious Diseases

Background:

• Multidrug-resistant (MDR) Gram-negative (GN) ESKAPE pathogens cause challenging pneumonia.
• Antimicrobial proteins (AMPs) show promise but face limitations like instability and poor pharmacokinetics.
• Existing AMP conjugates can cause excessive biomacromolecule interaction, reducing therapeutic efficacy.

Purpose of the Study:

• To develop a stable and effective nanomedicine for MDR Gram-negative pneumonia.
• To overcome AMP limitations including instability, narrow spectrum, and poor delivery.
• To enhance AMP penetration through respiratory tract mucus and reduce inflammation.

Main Methods:

• Screening of an ultra-acid-sensitive diblock copolymer-lysozyme conjugate to form LPOBE micelles.
• Evaluation of LPOBE's stability, nonfouling ability, and bactericidal activity in acidic conditions.
• Development of LPOBEN by loading sodium butyrate (NaBu) for improved mucus penetration and anti-inflammatory effects.

Main Results:

• LPOBE micelles demonstrated enhanced stability and potent bactericidal activity, reducing three MDR GN ESKAPE strains by 99.9%.
• Protonated LPOBE exhibited good serum protein-nonfouling ability in acidic conditions.
• LPOBEN showed improved mucus penetration and anti-inflammatory effects, addressing challenges in inhalation delivery for pneumonia treatment.

Conclusions:

• The developed LPOBE and LPOBEN systems offer a novel strategy for high-performance AMP-based nanomedicines.
• This approach provides a new theoretical foundation for treating MDR bacterial pneumonia.
• LPOBEN effectively enhances AMP stability, delivery, and therapeutic outcomes in a preclinical model.