A Universal Single‐Activated‐Dual‐Release Vehicle: Enabling Synergistic Antitumor Therapy

Abstract Activatable combined therapeutic strategy exhibits significant potential for the management of malignant tumors. Ensuring the timely and spatially effective release of different therapeutic agents is a great challenge for maximizing the efficacy of combination therapy. Herein, based on the 1,4‐and 1,6‐elimination behaviors, the study proposes a novel universal single‐activated‐dual‐release platform that can be triggered by various stimulants of interest. As a proof‐of‐concept, the study develops an example of a synergistic therapy called CyI‐Cbl‐NTR , which can be selectively activated by nitroreductase (NTR) to release the photosensitizer ( CyI‐OH ) and DNA alkylating agent chlorambucil (Cbl), thereby enabling a combination of chemo‐ and photodynamic therapy. Both in vitro and in vivo experiments fully demonstrate the remarkable combined therapeutic effect of Cyl‐Cbl‐NTR and the feasibility of this strategy. This work provides a promising platform for the future development of activatable synergistic therapy.