Macrophage Membrane‐Coated Nanoparticles Sensitize Glioblastoma to Radiation by Suppressing Proneural–Mesenchymal Transformation in Glioma Stem Cells

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AbstractRadiotherapy is identified as a crucial treatment for patients with glioblastoma, but recurrence is inevitable. The efficacy of radiotherapy is severely hampered partially due to the tumor evolution. Growing evidence suggests that proneural glioma stem cells can acquire mesenchymal features coupled with increased radioresistance. Thus, a better understanding of mechanisms underlying tumor subclonal evolution may develop new strategies. Herein, data highlighting a positive correlation between the accumulation of macrophage in the glioblastoma microenvironment after irradiation and mesenchymal transdifferentiation in glioblastoma are presented. Mechanistically, elevated production of inflammatory cytokines released by macrophages promotes mesenchymal transition in an NF‐κB‐dependent manner. Hence, rationally designed macrophage membrane‐coated porous mesoporous silica nanoparticles (MMNs) in which therapeutic anti‐NF‐κB peptides are loaded for enhancing radiotherapy of glioblastoma are constructed. The combination of MMNs and fractionated irradiation results in the blockage of tumor evolution and therapy resistance in glioblastoma‐bearing mice. Intriguingly, the macrophage invasion across the blood‐brain barrier is inhibited competitively by MMNs, suggesting that these nanoparticles can fundamentally halt the evolution of radioresistant clones. Taken together, the biomimetic MMNs represent a promising strategy that prevents mesenchymal transition and improves therapeutic response to irradiation as well as overall survival in patients with glioblastoma.