In the context of glioblastoma (GBM), hypoxia and inflammation are two main players of the tumor microenvironment. Hypoxia stimulates various features involves in tumor growth and also maintains a specific environment that favors protumor macrophages. Therefore, targeting hypoxia could potentially restore an anti-tumor M1 phenotype in macrophages. Besides, iron demonstrated its capacity to stimulate the polarization of macrophages towards an M1-like phenotype. In this paper we took advantages of microporous nanoparticles to co-deliver both oxygen and iron to bone marrow derived macrophages (BMDM) enabling the investigation of changes in polarization status and proteomic profiles. The nanoparticles were used in two in vivo models of glioblastoma, specifically, in both immunodeficient and immunocompetent settings. Our in vitro findings revealed that iron doped nanoparticles, saturated with oxygen were deemed safe for macrophages but did not demonstrate the capacity to change the M1 or M2 phenotypes. However, these nanoparticles induced some changes in proteomics pathways. The present study reports on in vivo experimentation that revealed the effects of nanoparticles on the hypoxic fraction, tumor volume, and macrophage phenotype in a GBM model. The findings indicated that the presence of nanoparticles led to a reduction in the hypoxic fraction in one of the GBM models, while no significant changes were observed in the tumor volume or macrophage phenotype. The present data showed that nanoparticles possess the capability of delivering both oxygen and iron to macrophages; though, they do not possess the ability to effectively repolarize M2 macrophages. Such strategies could be used in conjunction with other potent molecules to avoid M1 macrophages to inevitably differentiate to M2 macrophages.