Lanthanide Nanoparticles With Dual Enzyme Mimetic Activities for Targeted Treatment of Gram‐Negative Bacterial Infections

Abstract

Gram‐negative (G − ) bacterial infections, fueled by intrinsic antibiotic resistance stemming from their unique outer membrane architecture, pose a critical global clinical challenge. This study introduces a pioneering dual‐enzyme‐mimetic nanotherapy based on NaYbF 4 nanoparticles (NaYbF 4 NPs) that achieves synergistic antibacterial and anti‐inflammatory effects, circumventing conventional antibiotic resistance mechanisms. The NaYbF 4 NPs exhibit two distinct enzyme‐like activities: phospholipase C (PLC)‐like activity and alkaline phosphatase (ALP)‐like activity. The former (PLC‐like activity) specifically hydrolyzes phosphate groups in bacterial outer membrane phospholipids, inducing lethal membrane permeabilization, membrane potential collapse, and adenosine triphosphate (ATP) synthesis inhibition. This results in a 3.21 log 10 reduction in multidrug‐resistant (MDR) Escherichia coli viability and a 3.62 log 10 reduction in MDR Pseudomonas aeruginosa viability. The latter (ALP‐like activity) efficiently degrades lipopolysaccharide (LPS) endotoxins released during bacterial lysis. By blocking toll‐like receptor 4 (TLR4) pathway activation, it reduces the secretion of interleukin‐6 (IL‐6) and interleukin‐1β (IL‐1β) in murine monocyte‐macrophage (RAW 264.7) cells by 35.66% and 91.11%, respectively, thereby mitigating infection‐induced inflammatory reaction. In vivo assessment in a murine model of MDR Escherichia coli ‐infected skin wounds demonstrates that this strategy significantly accelerated wound healing without inducing systemic toxicity or adverse tissue reactions. By targetedly disrupting bacterial membranes to overcome resistance mechanisms while precisely modulating inflammatory responses, this “bactericidal‐anti‐inflammatory” dual‐mode strategy presents a reference framework for the design of anti‐infection agents.