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The interaction between nanoparticles (NPs) and bacterial cell envelopes is crucial for designing effective antibacterial materials against multi-drug-resistant pathogens. However, the current understanding assumes a uniform bacterial cell wall. This study challenges that assumption by investigating how bacterial cell wall curvature impacts antibacterial NP action. Focusing on Janus NPs, which feature segregated hydrophobic and polycationic ligands and previously demonstrated high efficacy against diverse bacteria, we found that these NPs preferentially target and disrupt bacterial poles. Experimental and computational approaches reveal that curvature at E. coli poles induces conformational changes in lipopolysaccharide (LPS) polymers on the outer membrane, exposing underlying lipids for NP-mediated disruption. We establish that curvature-induced targeting by Janus NPs depends on the outer membrane composition and is most pronounced at physiologically relevant LPS densities. This work demonstrates that high-curvature regions of bacterial cell walls are “weak spots” for Janus NPs, thereby aiding the development of more effective targeted therapies. 

Background Nanoparticles (NPs) hold promise as alternatives to antibiotics in the fight against multi-drug-resistant bacteria. However, concerns about their cytotoxicity, particularly their effects on mammalian cells, must be thoroughly addressed to ensure therapeutic safety. Amphiphilic Janus NPs, which have segregated hydrophobic and polycationic ligands on two hemispheres, have previously been shown to exhibit potent antibacterial activity. Methods In this study, we evaluated the cytotoxicity of amphiphilic Janus NPs in immune and cancer cell lines. Cytotoxicity assays were performed to assess the effects of Janus NPs on cell viability and membrane integrity, with a particular focus on how internalization of the nanoparticles influenced cellular responses. Results The results revealed that both immune and cancer cells exhibited negligible cytotoxic effects when exposed to Janus NPs. However, phagocytic immune cells demonstrated greater susceptibility to membrane damage and viability loss, suggesting that internalization plays a significant role in nanoparticle-induced cytotoxicity. Conclusions Amphiphilic Janus NPs show great potential as highly effective antibacterial agents with minimal cytotoxicity. While immune cells may be more vulnerable to nanoparticle-induced damage due to their internalization capacity, these findings support the further investigation of Janus NPs for clinical applications.