Autophagy-Enhanced Nanoplatforms Eliminate Intracellular Bacteria and Block Bacteria-Driven Epithelial-Mesenchymal Transition for Tumor Metastasis Inhibition.

Abstract

Tumor intracellular bacteria are a key driving force of epithelial-mesenchymal transition (EMT) in tumor cells, and EMT is a critical process in the metastasis cascade. Eliminating intracellular bacteria is a prospective therapeutic target for metastasis. However, existing targeted antibacterial approaches against intracellular bacteria, such as antibiotics, face challenges including drug resistance, biological barriers, or side effects. Here, we develop a tumor-targeted nanoplatform (HSO-OMDs) loaded with autophagy-induced metformin, docosahexaenoic acid, and chemotherapeutic drug oxaliplatin conjugated to hyaluronic acid, which enhances tumor cell autophagy for the effective elimination of intracellular bacteria. HSO-OMDs enhance autophagy by promoting the maturation of autophagosome, the fusion of autophagosomes and lysosomes, and the acidification of lysosomes in tumor cells. As a result, HSO-OMDs effectively eliminate intracellular bacteria by autophagy for blocking EMT processes and inhibit both primary tumor and metastasis. Collectively, our strategy against intracellular-bacteria-driven EMT by enhancing tumor cell autophagy provides a prospective approach for metastatic cancer treatment.