Oxygen Nanobubbles\nHalt Tumor Aggression and Metastasis\nby Inhibiting Hypoxia-Induced Epithelial-to-Mesenchymal Transition\nin Lung and Mammary Adenocarcinoma

The rapid proliferation of cancer cells creates a hypoxic\nmicroenvironment\nin solid tumors, driving aggressiveness through epithelial-to-mesenchymal\ntransition (EMT), invasion, and migration, often leading to resistance\nto conventional chemotherapies. Delivering oxygen directly to the\ntumor site can address these challenges. Herein, we fabricated liposomal\nencapsulated oxygen nanobubbles (L-ONBs) with nanoscale size that\nexhibit enhanced stability and efficient oxygen release. Characterization\nrevealed that the robust stability and negative surface charge of\nL-ONB particles prevent aggregation and facilitate passive targeting\nto tumor tissues due to the enhanced permeability and retention effect,\nthereby significantly reducing the aggressiveness of lung and breast\ntumors. Oxygen nanobubbles countered the hypoxia-induced EMT pathway\nby facilitating prolyl hydroxylation of hypoxia-inducible factor 1α,\nleading to its proteasomal degradation. This process resulted in the\nupregulation of epithelial marker E-cadherin and the downregulation\nof mesenchymal markers such as N-cadherin and vimentin, along with\na significant decrease in transforming growth factor-β and vascular\nendothelial growth factor-A. Overall, our study elucidates the cellular\nmechanisms by which L-ONBs inhibit hypoxia-induced tumor aggressiveness,\nhighlighting their potential as a promising therapeutic option for\nmanaging solid tumors.