Stimuli responsive nanoplatform with mitochondria-specific multiple model therapeutics for effective tumor treatment

Abstract Even chemotherapeutics could be transported to solid tumor by various tumor-targeted nanoplatforms, the therapeutic potency of chemotherapy is still plagued by tumor resistance to anti-tumor drugs. Herein, a dual-targeted core-shell nanoplatform (PDA-TPP-Fe-HA-DOX) with enzyme-triggered doxorubicin (DOX) release for accurate chemotherapy, mitochondria-specialized Fenton reaction for catalytic medicine and appositional photothermal therapy was fabricated, where the latter two functions not only activate individually to kill tumor cells but also damage mitochondria to reduce the drug resistance, resulting in further enhancement of chemotherapy. The nanoplatform can be internalized by solid tumor through CD44-mediated targetability due to the doxorubicin conjugated hyaluronic acid (HA-DOX) shell. After the initial degradation of the HA-DOX shell by over-expressed HAase in tumor cells to exert the accurate chemotherapy, the exposed core (PDA-TPP-Fe) would rapidly target the mitochondria via the TPP, following with Fenton reaction (catalyzed by Fe) and photothermal conversion (endowed by PDA) in mitochondria to further promote the apoptosis of the tumor cells. Both in vitro and in vivo experiments show that our dual-targeted core-shell nanoplatforms could perform an excellent tumor inhibition for tumor therapy.