Oxygen Nanobubbles Halt Tumor Aggression and Metastasis by Inhibiting Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Lung and Mammary Adenocarcinoma

Abstract

The rapid proliferation of cancer cells creates a hypoxic microenvironment in solid tumors, driving aggressiveness through epithelial-to-mesenchymal transition (EMT), invasion, and migration, often leading to resistance to conventional chemotherapies. Delivering oxygen directly to the tumor site can address these challenges. Herein, we fabricated liposomal encapsulated oxygen nanobubbles (L-ONBs) with nanoscale size that exhibit enhanced stability and efficient oxygen release. Characterization revealed that the robust stability and negative surface charge of L-ONB particles prevent aggregation and facilitate passive targeting to tumor tissues due to the enhanced permeability and retention effect, thereby significantly reducing the aggressiveness of lung and breast tumors. Oxygen nanobubbles countered the hypoxia-induced EMT pathway by facilitating prolyl hydroxylation of hypoxia-inducible factor 1α, leading to its proteasomal degradation. This process resulted in the upregulation of epithelial marker E-cadherin and the downregulation of mesenchymal markers such as N-cadherin and vimentin, along with a significant decrease in transforming growth factor-β and vascular endothelial growth factor-A. Overall, our study elucidates the cellular mechanisms by which L-ONBs inhibit hypoxia-induced tumor aggressiveness, highlighting their potential as a promising therapeutic option for managing solid tumors.