Hyaluronidase inhibitor surface-modified niosomes: An efficient strategy for antibacterial and anti-biofilm drug delivery

Bacterial infections caused by resistant strains have become one of the most significant life-threatening challenges. Therefore, the exploration of competent approaches is instantly required. We report multifunctional niosomes loaded with vancomycin (VCM) antibiotic and coated with antibacterial polyhexanide layer (pH) followed by a novel antivirulence polymer hyaluronic acid-N,N-Dibutylethylenediamine (HD), which exhibited efficient in vitro and in vivo anti-methicillin-resistant Staphylococcus aureus (MRSA) activity. HD-pH-coated niosomes had an average diameter, polydispersity index, zeta potential, and drug encapsulation efficiency of 153.7 & PLUSMN; 2.1 nm, 0.29 & PLUSMN; 0.04, -9.46 & PLUSMN; 1.46 mV and 84.15 & PLUSMN; 1.11%, respectively. The in vitro release showed a diffusion-based controlled VCM release profile. The binding affinity studies using Microscale thermophoresis and in silico techniques showed that HD competitively inhibited hyaluronate lyase enzyme even in the presence of its natural substrate, hyaluronic acid, resulting in better inhibition of colonization and biofilm formation of hyaluronate lyase producing bacteria. HD-pH-coated niosomes exhibited higher antibacterial and antibiofilm activity than the bare VCM and non-coated niosomes. Furthermore, the time-kill assay revealed a fast inhibition of bacterial growth with complete elimination of MRSA bacteria within the first 2 h of the study. In vivo studies against a mouse model of MRSA skin infection indicated that HD-pH-coated niosomes had a 29.6-fold reduction in MRSA load compared to bare VCM (p = 0.0006). Therefore, HD-pH coating was confirmed as a promising strategy for enhancing antibacterial and anti-biofilm drug delivery systems.