Infections with multidrug-resistant (MRD) Gram-negative bacteria, such as MRD Escherichia coli (E. coli), remain a challenge due to the lack of safe antibiotics and high fatality rates under anti-infection therapies. This work presents a form of biomimetic intelligent catalysis inspired by the selective biocatalytic property of macrophages, consisting of an intelligent controlling center (a living macrophage, MΦ) and a Fenton reaction catalyst (Fe₃O₄@poly(lactic-co-glycolic acid) (PLGA) nanoparticles) for killing MDR E. coli without harming normal cells. The MΦ–Fe₃O₄@PLGA particles (i.e., the intelligent catalysis particles) exhibit selective biocatalysis activity toward MDR E. coli by producing H₂O₂ and lipid droplets (LDs). This process activates the lipid metabolism and glycan biosynthesis and metabolism pathways based on the result of RNA sequencing data analysis. The H₂O₂ further reacts with Fe₃O₄@PLGA to form highly toxic hydroxyl radicals (•OH), while the LDs contain antimicrobial peptides and can target MDR E. coli. The highly toxic •OH and antimicrobial peptides are shown to combat with MDR E. coli, such that the antibacterial efficiency of the MΦ–Fe₃O₄@PLGA particles against MDR E. coli is 99.29% ± 0.31% in vitro. More importantly, after several passages, the intelligent catalysis function of the MΦ–Fe₃O₄@PLGA particles is well maintained. Hence, the concept of biomimetic intelligent catalysts displays potential for treating diseases other than infections.