Hybrid Protein Nano‐Reactors Enable Simultaneous Increments of Tumor Oxygenation and Iodine‐131 Delivery for Enhanced Radionuclide Therapy

It is hard for current radionuclide therapy to render solid tumors desirable therapeutic efficacy owing to insufficient tumor‐targeted delivery of radionuclides and severe tumor hypoxia. In this study, a biocompatible hybrid protein nanoreactor composed of human serum albumin (HSA) and catalase (CAT) molecules is constructed via glutaraldehyde‐mediated crosslinking. The obtained HSA‐CAT nanoreactors (NRs) show retained and well‐protected enzyme stability in catalyzing the decomposition of H2O2 and enable efficient labeling of therapeutic radionuclide iodine‐131 (131I). Then, it is uncovered that such HSA‐CAT NRs after being intravenously injected into tumor‐bearing mice exhibit efficient passive tumor accumulation as vividly visualized under the fluorescence imaging system and gamma camera. As the result, such HSA‐CAT NRs upon tumor accumulation would significantly attenuate tumor hypoxia by decomposing endogenous H2O2 produced by cancer cells to molecular oxygen, and thereby remarkably improve the therapeutic efficacy of radionuclide 131I. This study highlights the concise preparation of biocompatible protein nanoreactors with efficient tumor homing and hypoxia attenuation capacities, thus enabling greatly improved tumor radionuclide therapy with promising potential for future clinical translation. A hybrid protein nanoreactor, composed of human serum albumin and catalase molecules, shows well‐protected enzyme stability in catalyzing the decomposition of H2O2 and enables efficient labeling of therapeutic radionuclide iodine‐131 (131I). Upon intravenous injection, this hybrid nanoreactor endows tumor‐targeted delivery of therapeutic 131I and efficient tumor reoxgenation, thus leading to enhanced radionuclide therapy.