Nanobubble-Mediated Oxygen Delivery Mitigates Hypoxia-Induced ROS and HIF-1α Expression in UC-MSCs

Hypoxia and nutrient-deprived microenvironments pose significant challenges to the survival of transplanted human umbilical cord mesenchymal stem cells (UC-MSCs), necessitating the development of controllable oxygen delivery strategies. In this study, we engineered fluorosurfactant-coated oxygen nanobubbles (Tivida^®-stabilized; TONBs) and assessed their cytoprotective effects in a two-dimensional (2D) ischemia-mimetic model (1% O₂ and 1% FBS). The TONBs were characterized by nanoparticle tracking analysis and zeta potential, while dissolved oxygen (DO) release was quantified in DMEM culture media. TONBs formed stable sub-200 nm populations with high colloidal stability (−58 mV) and demonstrated elevated DO levels up to ~18 ppm, compared to DMEM control (~ 8 ppm). Under hypoxic stress, TONB treatment preserved metabolic activity and viability, reduced mitochondrial ROS levels by ~20% and resulted in an ~8–9 fold downregulation of HIF-1α expression relative to untreated hypoxic controls. These results indicate that TONBs provide oxygen buffering to mitigate hypoxia-driven metabolic stress, supporting their potential as an oxygen delivery adjunct for regenerative medicine applications and tissue engineering applications.