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

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 (CaO₂@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 (CaO₂) 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 (Ca²⁺), doxorubicin (DOX), catalase (CAT), and coincidentally produces a large amount of hydrogen peroxide (H₂O₂) in the acidic tumor microenvironment (TME) containing hyaluronidase. Subsequently, CAT can catalyze the transformation of H₂O₂ into oxygen (O₂) ameliorating the hypoxia. Ca²⁺-overloading-induced mitochondrial dysfunction can interrupt ATP synthesis and restrain cellular respiration decreasing O₂ 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.