Repurposing Erythrocytes as a “Photoactivatable Bomb”: A General Strategy for Site‐Specific Drug Release in Blood Vessels

Abstract Tumor vasculature has long been considered as an extremely valuable therapeutic target for cancer therapy, but how to realize controlled and site‐specific drug release in tumor blood vessels remains a huge challenge. Despite the widespread use of nanomaterials in constructing drug delivery systems, they are suboptimal in principle for meeting this demand due to their easy blood cell adsorption/internalization and short lifetime in the systemic circulation. Here, natural red blood cells (RBCs) are repurposed as a remote‐controllable drug vehicle, which retains RBC's morphology and vessel‐specific biodistribution pattern, by installing photoactivatable molecular triggers on the RBC membrane via covalent conjugation with a finely tuned modification density. The molecular triggers can burst the RBC vehicle under short and mild laser irradiation, leading to a complete and site‐specific release of its payloads. This cell‐based vehicle is generalized by loading different therapeutic agents including macromolecular thrombin, a blood clotting‐inducing enzyme, and a small‐molecule hypoxia‐activatable chemodrug, tirapazamine. In vivo results demonstrate that the repurposed “anticancer RBCs” exhibit long‐term stability in systemic circulation but, when tumors receive laser irradiation, precisely releases their cargoes in tumor vessels for thrombosis‐induced starvation therapy and local deoxygenation‐enhanced chemotherapy. This study proposes a general strategy for blood vessel‐specific drug delivery.