Multimodal Nanoplatform with ROS Amplification to Overcome Multidrug Resistance in Prostate Cancer via Targeting P‐Glycoprotein and Ferroptosis

Abstract Chemotherapy remains the most essential treatment for prostate cancer, but multidrug resistance (MDR) contributes to chemotherapy failure and tumor‐related deaths. The overexpression of P‐glycoprotein (P‐gp) is one of the main mechanisms behind MDR. Here, this work reports a multimodal nanoplatform with a reactive oxygen species (ROS) cascade for gas therapy/ferroptosis/chemotherapy in reversing MDR. The nanoplatform disassembles when responding to intracellular ROS and exerts three main functions: First, nitric oxide (NO) targeted delivery can reverse MDR by downregulating P‐gp expression and inhibiting mitochondrial function. Second, ferrocene‐induced ferroptosis breaks the redox balance in the tumor intracellular microenvironment and synergistically acts against the tumor. Third, the release of paclitaxel (PTX) is precisely controlled in situ in the tumor for chemotherapy that avoids damage to normal tissues. Excitingly, this multimodal nanoplatform is a promising weapon for reversing MDR and may provide a pioneering paradigm for synergetic cancer therapy.