Reversing Multidrug Resistance via Efficient Inhibition of Drug Efflux for Enhanced Cancer Therapy

ABSTRACT Multidrug resistance (MDR) mediated by P‐glycoprotein (P‐gp) remains a primary obstacle for successful cancer chemotherapy. Effective inhibition of P‐gp transport is important for high efficacy of chemotherapeutic drugs. Herein, a smart platform (CaO 2 @HA‐CAT‐DOX‐FA) is proposed to reduce the expression of P‐gp through the combination of hypoxia alleviation and adenosine triphosphate (ATP) suppression, thereby effective diminishing the efflux of chemotherapeutic drug. Hyaluronic acid (HA) can protect calcium peroxide (CaO 2 ) from premature depletion. The nanocomposite is further conjugated with folic acid (FA) to endow it with tumor‐targeting ability. At the tumor site, the nanocomposite disintegrates and releases calcium ion (Ca 2+ ), doxorubicin (DOX), catalase (CAT), and coincidentally produces a large amount of hydrogen peroxide (H 2 O 2 ) in the acidic tumor microenvironment (TME) containing hyaluronidase. Subsequently, CAT can catalyze the transformation of H 2 O 2 into oxygen (O 2 ) ameliorating the hypoxia. Ca 2+ ‐overloading‐induced mitochondrial dysfunction can interrupt ATP synthesis and restrain cellular respiration decreasing O 2 consumption. With the combination of relieving hypoxia and suppressing ATP production, the expression of P‐gp was remarkable downregulated, thereby overcoming MDR, with confirmed by in vitro and in vivo experiments. This study may provide new avenues for the treatment of multidrug‐resistant tumors.