Engineering Red Blood Cells for Amplified Tumor Dual‐Gas Transfusion Therapy

Red blood cell (RBC) transfusion therapy constitutes a vital medical intervention primarily aimed at enhancing oxygen delivery. Furthermore, RBCs possess the ability to stably bind therapeutic gas molecules such as carbon monoxide (CO) and nitric oxide (NO). As natural gas carriers, RBCs have the potential to mitigate the non-specific gas release and biosafety issues associated with conventional gas donors, which currently hinder the clinical application of gas therapy. In this study, RBCs are innovatively engineered for amplified tumor dual-gas transfusion therapy. The RBCs delivering CO and NO are developed using advanced nano- and gas-engineering techniques. These engineered RBCs are activated by tumor cell-specific hydrogen peroxide (H₂O₂) to release gases, and it induces a cascade amplification of reactive oxygen species (ROS) and reactive nitrogen species (RNS) (ONOO^-) production through the catalytic action of the ferrous hemoglobin (HbFe²⁺). This process disrupts glycometabolism and reshapes the tumor immunosuppressive microenvironment, thereby enhancing therapeutic efficacy. By integrating tumor cell membrane engineering, this approach enables targeted, personalized therapy and effectively suppresses metastatic tumors synergistically with αPD-L1. Comprehensive evaluation demonstrates that engineered RBC-based amplified tumor dual-gas transfusion therapy exhibits excellent biosafety, and holds significant potential as a highly translatable and promising cancer treatment modality.