Natural Enzyme‐Loaded Polymeric Stealth Coating‐Armed Engineered Probiotics by Disrupting Tumor Lactate Homeostasis to Synergistic Metabolism‐Immuno‐Enzyme Dynamic Therapy

Abstract

Reducing L-lactate levels in tumors is crucial for alleviating immunosuppression and enhancing treatment efficacy. Recently, bacteria have great potential in improving lactate levels in the tumor microenvironment due to their physiological properties, tumor tropism, and immunogenicity. However, developing bacterial-based lactate regulation platforms is still facing great challenges due to bacterial modification impacts on activity, macrophage phagocytosis, and complex tumor microenvironment. Herein, an engineered Lactobacillus acidophilus (LH@LA) is developed, armed with a polymeric stealth coating that co-loads lactate oxidase (LOx) and horseradish peroxidase (HRP). This coating protects bacteria from macrophage phagocytosis, maintaining their activity for deep tumor drug delivery. And then, LOx and HRP can consume much L-lactate in the tumor site through an enzyme cascade reaction to improve the immunosuppressive environment, while causing oxidative stress and reduced ATP supply, thereby reversing AKT-mTOR metabolic pathway activation to inhibit tumor growth. More interestingly, LA not only acts as a natural enzyme's carrier, but also induces anti-inflammatory M2 macrophages to polarize into pro-inflammatory M1 macrophages by secreting D-lactate, enhancing antitumor immunotherapy. This engineered probiotic design provides a new idea for building a safe and efficient live bacteria delivery platform, providing a reference for developing cancer treatment strategies with clinical translation prospects.