Hyperbaric Oxygen Regulates Tumor pH to Boost Copper‐Doped Hydroxyethyl Starch Conjugate Nanoparticles Against Cancer Stem Cells

ABSTRACT An extracellular acidic environment and an intracellular mildly alkaline environment induced by carbonic anhydrase 9 (CA9) play a critical role in self‐renewal, invasion, migration, and drug resistance of cancer stem cells (CSCs) within hypoxic solid tumors. Here, we report an antitumor strategy leveraging hyperbaric oxygen therapy (HBO) to regulate tumor pH and boost hydroxyethyl starch‐doxorubicin‐copper nanoparticles (HHD‐Cu NPs) against CSCs. HBO overcomes tumor hypoxia, downregulates pH‐regulatory proteins such as CA9, and leads to intracellular accumulation of acidic metabolites. As a result, HBO promotes intracellular acidification of both tumor cells and CSCs, triggering efficient doxorubicin release and the potent copper‐mediated chemical dynamic effect of subsequently administered dual‐acid‐responsive HHD‐Cu NPs. The combination of HBO with HHD‐Cu NPs not only eliminates tumor cells but also inhibits CSCs, altogether leading to potent tumor inhibition. This study explores a new function of clinical‐widely used HBO and establishes a novel combination therapy for treating CSCs abundant hypoxic solid tumors.