Rapamycin-reinforced ferroptosis assisted by a lysosome-controlled disintegratable micelle in autophagy-dependent/independent manners

Upregulating the susceptibility of cancer cells to ferroptosis is crucial to upgrade anti-cancer efficiency of ferroptosis drug system. At present, optimizing the sensitizer for ferroptosis with expected mechanism and improved transport via facile nanocarriers still heavily rely on serendipitous discovery and repetitious assignment. Herein, we employ the tannic acid (TA)-templated silicon nanoparticle as nanocore to descend the lysosome-controlled disintegratable Fe3+@[email protected] micelles (REFSM) to identify rapamycin as a ferroptosis sensitizer through autophagy-dependent/independent pathways. The as-prepared REFSM dissociates responding to the acidic condition and enzyme system of lysosomes, permitting Fe3+ and erastin release to irritate ferroptosis, which is reinforced by released rapamycin via irritating ferritinophagy and lipophagy, and suppressing HIF-1α. The rapamycin-reinforced ferroptosis is demonstrated to be specific to H2O2-overloaded cancer cells. Moreover, the introduction of rapamycin reduces the positive charge of micelle and improves its distribution in tumors. Both the controllable dissociation and the improved charge of REFSM ensure its anti-cancer efficiency at trace amount of erastin (0.3 mg kg−1) and rapamycin (2.2 mg kg−1) and minimize the systematic toxicity. This archetypical template provides a versatile platform for rapamycin as sensitizer to enhance ferroptosis by displaying its multiple pharmacological mechanism, controlling its release and improving its distribution in vivo.