A Self-Propelled Molecular Rocket Triggers Ferroptosis and Apoptosis for Improving Herceptin Resistance in Cancer Therapy.

To overcome the Herceptin resistance in breast cancer and avoid toxicity to normal cells of triptolide (TP). Herein, an acid-switched self-propelled molecular rocket (TPBoc) for enhanced cancer treatment through the synergy both ferroptosis/apoptosis and mechanics was designed. Generally, TPBoc exhibited low toxicity on normal cells/tissues due to the selective block of the toxic group. Acid-triggered tert-butoxy carbonyl (Boc) group was removed by acidic tumor microenvironment, releasing the highly toxic TP and CO2, whose thrust forces propelled motion and diffusion of TP like a launched rocket, promoting drug infiltration into tumor tissues. The released TP could induce apoptosis and ferroptosis via Nrf-2-SLC7A11-GSH pathway, promoting membrane lipid peroxidation, thus enhancing the therapeutic effect of Herceptin on drug-resistant tumor cells. Both in vitro and in vivo results demonstrated that the self-propelled molecular rocket could not only perform superior specificity and excellent therapeutic outcomes, but also show good drug-likeness. Overall, the acid-switched self-propelled molecular rocket provided an efficient new therapeutic strategy for cancer treatment by virtue of the synergistic effect of ferroptosis/apoptosis and propelled motion.