RNA‐Seq Reveals the Mechanism of Synergistic Hydrogen‐Chemotherapy Based on Active Magnesium Micromotors for Inhibiting Glioblastoma Recurrence by Modulating Tumor Microenvironment

Abstract Postoperative recurrence of glioblastoma (GBM) is a key contributing factor to the unfavorable prognosis of patients. Chemotherapy has been extensively employed as a postoperative treatment for GBM; however, the produced drug resistance significantly undermines the chemotherapeutic efficacy. Herein, a multifunctional system based on magnesium micromotor (Mg‐Motor‐DOX) is designed and fabricated that can generate hydrogen gas in situ and actively deliver the chemotherapeutic drug doxorubicin (DOX). Utilizing a temperature‐sensitive hydrogel, Mg‐Motor‐DOX is administrated in situ to the residual cavity of the tumor after subtotal GBM resection. The produced H₂ by the Mg‐water reaction not only propels the motion of motors but also functions as an antioxidant to effectively alleviate the neuroinflammation caused by GBM resection. The H₂ bubbles create a pronounced vortex flow in situ, greatly enhancing the DOX penetration and the sensitivity of GBM cells to DOX. Therefore, synergistic hydrogen‐chemotherapy significantly inhibits the recurrence of the in situ GBM model. RNA‐Seq technology further elucidates the role of the strategy in modulating the tumor immune microenvironment via converting cold tumors into hot tumors, thereby establishing a theoretical foundation for the clinical implementation of synergistic hydrogen‐chemotherapy.