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

Abstract Solid tumors possess a unique internal environment with high‐level thiols (mainly glutathione), over‐expressed H 2 O 2 , 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 MnO 2 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 MnO 2 layer responds with H 2 O 2 and glutathione to release oxygen and generate •OH, thereby alleviating hypoxia and achieving chemodynamic therapy (CDT). Afterward, the strong coordination between Bi 3+ 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 T 1 ‐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.