Modulating cationic-hydrophobic balance in hydrogel polymer nanoparticles for enhanced membrane interactions and...

Cationic amphiphilic polymers have shown great potential in addressing public health challenges posed by drug-resistant bacteria. However, achieving high antibacterial efficacy requires precise regulation of the cationic-hydrophobic balance through rational monomer selection. Herein, we synthesized a library of hydrogel polymer nanoparticles (HNPs) by incorporating different cationic (MArg, MLys, MHis) and hydrophobic (C2, C4, C6, C8) monomers, aiming to explore the roles of these monomers in regulating the cationic-hydrophobic balance and thereby the antibacterial performance of the HNPs. Potent antibacterial efficacy was achieved for C4-MArg HNPs (nearly 100 % mortality against E. coli and S. aureus at HNP doses of 5 and 2.5 μg/mL, respectively) as an optimal cationic-hydrophobic balance was attained between MArg and C4 moieties with no mutual shielding or antagonistic effects from steric hindrance. Polymer-bacterium interactions, predominantly electrostatic forces, triggered bacterial aggregation, which correlated positively with the surface potentials of the HNPs. C4-MLys HNPs with the highest surface potential (+82.5 mV) showed the highest bacterial adhesion efficiency (over 80 % at a dose of 5.0 μg/mL within 30 min). These HNPs induced bacterial death through binding to lipopolysaccharides or lipoteichoic acids, disrupting bacterial membranes and causing cytoplasmic leakage. The screened C4-MArg HNPs demonstrated good biocompatibility and therapeutic efficacy, achieving a 50 % enhancement in survival rate compared to the control group in a murine systemic infection model. These findings establish precise modulation of the cationic-hydrophobic balance as a powerful strategy to optimize the antibacterial potency of HNPs, offering insights for the discovery, design and development of advanced broad-spectrum antibacterial materials.