Antibiotic vesicles based on peptide-polymer complex coacervation.

Antimicrobial peptides (AMPs) represent a promising strategy for developing new antibiotic formulations to combat multidrug-resistant bacterial infections. However, the therapeutic application of colistin, a potent AMP, is largely limited to last-resort scenarios due to its associated cytotoxicity and low stability in solution. In our investigation of complex coacervation techniques for creating effective drug delivery platforms, we discovered the formation of complex coacervate core vesicles (C3Vs) upon mixing cationic colistin with partially oppositely charged poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMAA) diblock copolymers. This approach opens new avenues for enhancing the therapeutic potential of colistin while mitigating its drawbacks. To gain deeper insights into these structures, we prepared C3Vs using both protonated and partially deuterated PEO-b-PMAA in combination with colistin. Through the development of a tailored analytical vesicle scattering model, we describe our small-angle X-ray and neutron scattering (SAXS/SANS) data and quantify the structure and composition of C3Vs for the first time in great detail. We report net-neutral vesicles with diameters of 100-190 nm with a fixed vesicle wall dimension that has a total nominal thickness of ≈ 17-18 nm. Notably, while the wall thickness remains invariant, the inner radius of the vesicle (water core) varies significantly with experimental conditions, such as concentration, charge fraction, incubation time, and ionic strength. Increasing the ionic strength to physiological levels, we find smaller assembled structures that resemble micelles rather than vesicles. Interestingly, time-resolved SANS experiments show that the vesicles in salt-free solution are exceptionally stable with no detectable exchange kinetics between vesicles within 24 hours. We expect the structural elucidation of these systems in multiple conditions to provide valuable insights for future research, particularly in developing vesicular drug delivery systems.