A Bioenvironment-Responsive Versatile Nanoplatform Enabling Rapid Clearance and Effective Tumor Homing for Oxygen-Enhanced Radiotherapy

Nanoradiosensitizer-augmented cancer radiotherapy (RT) has been widely investigated, whereas the desirable nanoradiosensitizer with the characteristics of rapid clearance, effective tumor homing, and tumor hypoxia relief is still lacking. Herein, bismuth sulfide–albumin composite nanospheres followed by catalase conjugation (denoted as BSNSs-CAT) have been well constructed as a bioenvironment-responsive nanoradiosensitizer platform. The BSNSs-CAT phagocytosed by normal cells demonstrate architectural disintegration into small ones in response to physiological pH, achieving small size-favored rapid clearance, which largely mitigates the concern of long-term toxicity of BSNSs-CAT in normal tissues. More importantly, benefiting from their large size-favored enhanced permeability and retention effect, BSNSs-CAT accumulate efficiently in tumors and remain architecturally stable in a mildly acidic tumor microenvironment (TME), which strongly favors a response with H 2 O 2 overproduced TME. As a result, the produced intratumor oxygen could overcome tumor hypoxia-associated RT resistance, together with the radiosensitization effect of bismuth, collectively enhancing RT efficacy. This research demonstrates a versatile material solution by fully exploring its bioenvironment-responsive nature, offering a new strategy for nanomedicine design and application.