Biohybrid nanorobots induce lactate isomer conversion to reverse the immune environment and promote tumor therapy.

Abstract

Tumor cell glycolysis produces high levels of l-lactate (l-LA), creating an immunosuppressive microenvironment that enhances tumor stemness and impairs the efficacy of cancer therapies. Current strategies to reduce l-LA are limited by physical barriers in solid tumors and resource waste. This study presents an intelligent nanorobot that not only enhances tumor targeting and deep penetration but also reprograms the tumor immune microenvironment to convert l-LA into immunostimulatory d-lactate (d-LA). The nanorobot uses gold nanoparticles to bridge palladium (Pd) nanozymes and <i>Lactobacillus crispatus</i>-derived outer membrane vesicles (CMVs). Pd nanozymes catalyze H₂O₂ into O₂, facilitating deep tumor penetration, whereas the acidic tumor microenvironment activates Pd nanozymes to produce hydroxyl radicals (·OH), inducing immunogenic cell death. CMVs, which are rich in d-lactate dehydrogenase and artificially introduce lactate oxidase, catalyze the conversion of l-LA to d-LA, reversing its immunosuppressive effects. Preclinical models demonstrate potent antitumor effects, enhancing the immune response and reshaping the tumor microbiome.