An "AND" Logic-Gated Prodrug Micelle Locally Stimulates Antitumor Immunity

Materials that can respond to multiple biomarkers simultaneously, acting as an "AND" gate, have the potential to enhance tumor-targeting for drug delivery. In this study, an "AND" logic-controlled release prodrug micelle is developed for codelivering the chemotherapeutic and the stimulator of interferon genes (STING) agonist, enabling precise combinatorial therapy. The drug release is programmed by tumor-enriched boramino acids (BAA) in the tumor microenvironment and intracellular reactive oxygen species (ROS), resulting in enhanced tumor targeting. STING agonist is successfully encapsulated into prodrug micelles through pi-pi stacking and hydrophobic interactions. These AND logic-gated prodrug micelles can achieve tumor-targeted delivery of STING agonist, leading to significantly enhanced immune activation and antitumor efficacy in vivo. It is expected that this clinically relevant nanoplatform will provide a rational design of an effective immunotherapy combination regimen to convert immunologically "cold" tumors to immunogenic "hot" tumors, addressing the major challenges faced by immunotherapies. In this study, a novel AND logic-controlled release prodrug micelle that integrates both external and internal stimuli is developed for codelivering chemotherapeutic agents, camptothecin (CPT), and stimulator of interferon genes (STING) agonists DMXAA, enabling precise combinatorial therapy. DMXAA is successfully encapsulated into prodrug micelles through pi-pi stacking and hydrophobic interactions, allowing for tumor-targeted delivery and significantly enhanced immune activation and antitumor efficacy.image