Optimizing Oxygen-Production Kinetics of Manganese Dioxide Nanoparticles Improves Hypoxia Reversal and Survival in Mice with Bone Metastases.

Persistent hypoxia in bone metastases induces an immunosuppressive environment, limiting the effectiveness of immunotherapies. To address chronic hypoxia, we have developed manganese dioxide (MnO) nanoparticles with tunable oxygen production kinetics for sustained oxygenation in bone metastases lesions. Using polyethylene glycol (PEG)-stabilized MnO or poly(lactic[50]--glycolic[50] acid) (50:50 PLGA), poly(lactic[75]--glycolic[25] acid) (75:25 PLGA), and polylactic acid (PLA)-encapsulated MnO NPs, we demonstrate that polymer hydrophobicity attenuates burst oxygen production and enables tunable oxygen production kinetics. The PEG-MnO NPs resulted in rapid hypoxia reduction in spheroids, which was rapidly attenuated, while the PLA-MnO NPs exhibited delayed hypoxia control in cancer spheroids. The 50:50 PLGA-MnO NPs exhibited the best short- and long-term control of hypoxia in cancer spheroids, resulting in sustained regulation of the expression of HIF-1α and immunosuppressive genes. The sustained control of hypoxia by the 50:50 PLGA-MnO NPs enhanced the cytotoxicity of natural killer cells against cancer spheroids. In vivo, 50:50 PLGA-MnO showed greater accumulation in the long bones and pelvis, common sites for bone metastases. The NPs decreased hypoxia in bone metastases and decreased regulatory T cell levels, resulting in enhanced survival of mice with established bone metastases.