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 H₂ O₂ , 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 H₂ O₂ 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.