Optimized Polymer-Lipid Hybrid Nanoparticles for Enhanced Delivery and Antibacterial Activity of Gentamicin Against Resistant Pathogens

Antibiotic resistance is a critical global health concern, driven by biofilm formation and the declining effectiveness of conventional therapies. This study investigates polymer-lipid hybrid nanoparticles (PLNs) as an innovative drug delivery system to enhance the antibacterial efficacy of gentamicin (Gen) while addressing challenges related to its hydrophilicity and encapsulation. Using an optimized double-emulsification/solvent-evaporation technique, PLNs were designed to improve drug entrapment efficiency (EE%) and loading capacity (DL%). The resulting formulations were characterized for particle size, polydispersity, zeta potential, and encapsulation efficiency. Transmitted electron microscopy (TEM) provided insights into particle morphology, while antibacterial activity was tested against multiple bacterial strains, including resistant isolates. The optimized formulation (F4) demonstrated significant improvements, achieving an EE% of 42%, a DL% of 7.2%, and uniform particle sizes (~143.4 nm) with high stability (zeta potential ~-38 mV) and a monodisperse distribution. TEM analysis confirmed Gen encapsulation within the lipid-polymer matrix. F4 exhibited notably enhanced antibacterial performance, particularly against Methicillin-resistant Staphylococcus aureus (MRSA-59) and Pseudomonas aeruginosa (PA-78), with up to a 160-fold reduction in minimum inhibitory/bactericidal concentrations (MIC/MBC) compared to free Gen. These findings underscore the potential of PLNs as a robust platform for targeted drug delivery, offering a promising strategy to combat antimicrobial resistance.