Tumor Microenvironment Modulation Platform Based on Composite Biodegradable Bismuth–Manganese Radiosensitizer for Inhibiting Radioresistant Hypoxic Tumors

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Solid tumors possess a unique internal environment with high‐level thiols (mainly glutathione), over‐expressed H2O2, and low oxygen partial pressure, which severely restrict the radiotherapy (RT) efficacy. To overcome the imperfections of RT alone, there is vital to design a multifunctional radiosensitizer that simultaneously achieves multimodal therapy and tumor microenvironment (TME) regulation. Bismuth (Bi)‐based nanospheres are wrapped in the MnO2 layer to form core–shell‐structured radiosensitizer (Bi@Mn) that can effectively load docetaxel (DTX). The solubility of Bi@Mn‐DTX is further improved via folic acid‐modified amphiphilic polyethylene glycol (PFA). Bi@Mn‐DTX‐PFA can specifically respond to the TME to realize multimodal therapy. Primarily, the outer MnO2 layer responds with H2O2 and glutathione to release oxygen and generate •OH, thereby alleviating hypoxia and achieving chemodynamic therapy (CDT). Afterward, the strong coordination between Bi3+ and deprotonated thiol groups in glutathione allows the mesoporous Bi‐containing core bonding with glutathione to form a water‐soluble complex. These actions conduce Bi@Mn‐DTX‐PFA degradation, further releasing DTX to implement chemotherapy (CHT). In addition, the degradation in vivo and tumor enrichment of Bi@Mn‐PFA are explored via T1‐weighted magnetic resonance and computed tomography imaging. The biodegradable composite Bi@Mn‐DTX‐PFA can simultaneously modulate the TME and achieve multimodal treatment (RT/CDT/CHT) for hypoxic tumors.