An enzyme-instructed self-assembly system induces tumor acidosis via sequential-dual effect for cancer selective therapy.

The acidosis anti-tumor therapy, based on the altered energy metabolism pathway of tumor cells, has been proposed as an attractive method for cancer selective treatment. However, the strategy of inducing tumor acidosis by using a single drug to simultaneously inhibit both lactate efflux and consumption has not been reported yet. Herein, an in situ enzyme-instructed self-assembly (EISA) system was rationally fabricated to induce tumor acidosis apoptosis for cancer selective therapy. Depending on the sequential effect of the in situ EISA system, the targeted drug was successively distributed on the membrane and intracellular, inhibiting MCT4 mediated lactate efflux and mitochondrial tricarboxylic acid (TCA) cycle mediated lactate consumption, respectively. Through the dual obstruction of lactate metabolism to trigger tumor acidosis, the in situ EISA nanomedicine showed selective growth and migration inhibition against cancer cells. In addition, the nanomedicine also displayed a radio-sensitization effect in vitro due to causing the mitochondrial dysfunction, and exhibited a prominent synergistic chemo-radiotherapy anti-tumor performance in vivo. Accordingly, this work demonstrated that the in situ EISA system could endow the LND with sequential-dual effects to induce tumor acidosis, which may provide an enlightening strategy for anticancer drug delivery and cancer selective therapy. STATEMENT OF SIGNIFICANCE: With the help of the sequential effect of in situ EISA , the serial attack of LND against different targets was effectively realized to induce tumor acidosis and combined chemo-radiotherapy, implying the importance of the relationship between structure and function, which could offer a distinctive inspiration for future drug delivery system design and anti-tumor application.