Exploiting Bacterial Metabolism for Targeted Antimicrobial Release from Smart Nanocarriers

Abstract Acidogenic and aciduric bacteria acidify their local microenvironment through carbohydrate metabolism, contributing to pathological microenvironment acidification in diseases, including dental caries, infection, and inflammation. We present a mesoporous silica nanoparticle platform equipped with surface-bound, pH-responsive gatekeepers that remain sealed at physiological pH yet rapidly release a drug payload under acidic conditions. This system converts a broad-spectrum antimicrobial into a selectively activated antimicrobial system: release is suppressed under neutral conditions and triggered when bacteria generate acid. In a human oral microbiome model, the nanoparticles selectively eradicate acid-producing bacteria, with metabolic acidification directly activating their own killing, as evidenced by simultaneous single-cell-scale fluorescence imaging of pH and viability. Mechanistic studies using proton NMR and contact angle measurements show that the gating mechanism relies on synergistic molecular interactions and hydrophilicity–hydrophobicity transitions. This work establishes an on-site antimicrobial strategy triggered by metabolic acidification for targeting microbes with undesirable metabolic features, thus paving the way toward more controlled infection therapies.