| Abstract: | Blocking cancer metabolism represents an attractive therapeutic strategy for cancer treatment. However, the lack of selective mitochondria targeting compromises the efficacy and safety of antimetabolic agents. Given that β‐glucuronidase (β‐G) is overexpressed in the tumor extracellular microenvironment and intracellular endosomes and lysosomes, a new concept of “pro‐staramine” is proposed to achieve multistage tumor mitochondrial targeting. The pro‐staramine, namely GluAcNA, is engineered by conjugating a β‐glucuronic acid to staramine via a “seamless” linker. When exposed to β‐G, the β‐glucuronic acid in GluAcNA can be hydrolyzed, followed by a rapid 1,6‐self‐elimination of the “seamless”, thus transforming anionic GluAcNA to cationic staramine. Liposomes containing GluAcNA (GluAcNA‐Lip) show long‐circulating characteristics and undergo a sequentially β‐G‐triggered activation, resulting in a cation‐driven mitochondrial accumulation. The multistage mitochondrial targeting and the promising antitumoral efficacy of GluAcNA‐Lip are validated by employing lonidamine as a model drug. |
