Seeking Cells, Targeting Bacteria: A Cascade‐Targeting Bacteria‐Responsive Nanosystem for Combating Intracellular Bacterial Infections

Abstract Intracellular bacteria pose a great challenge to antimicrobial therapy due to various physiological barriers at both cellular and bacterial levels, which impede drug penetration and intracellular targeting, thereby fostering antibiotic resistance and yielding suboptimal treatment outcomes. Herein, a cascade‐target bacterial‐responsive drug delivery nanosystem, MM@SPE NPs, comprising a macrophage membrane (MM) shell and a core of SPE NPs. SPE NPs consist of phenylboronic acid‐grafted dendritic mesoporous silica nanoparticles (SP NPs) encapsulated with epigallocatechin‐3‐gallate (EGCG), a non‐antibiotic antibacterial component, via pH‐sensitive boronic ester bonds are introduced. Upon administration, MM@SPE NPs actively home in on infected macrophages due to the homologous targeting properties of the MM shell, which is subsequently disrupted during cellular endocytosis. Within the cellular environment, SPE NPs expose and spontaneously accumulate around intracellular bacteria through their bacteria‐targeting phenylboronic acid groups. The acidic bacterial microenvironment further triggers the breakage of boronic ester bonds between SP NPs and EGCG, allowing the bacterial‐responsive release of EGCG for localized intracellular antibacterial effects. The efficacy of MM@SPE NPs in precisely eliminating intracellular bacteria is validated in two rat models of intracellular bacterial infections. This cascade‐targeting responsive system offers new solutions for treating intracellular bacterial infections while minimizing the risk of drug resistance.