NIR‐II Photothermal Activation of TRPV1 Channels for Intracellular Magnesium Regulation by Porous Pd@Pt Core–Shell Nanostructure to Reverse Tumor Multidrug Resistance

Abstract Multidrug resistance (MDR) caused by overexpressed P‐glycoprotein (P‐gp) in cell membrane is the main barrier for clinical tumor chemotherapy. P‐gp can pump the chemical drugs out of tumor cells depending on ATP‐provided energy. Herein, a photothermal‐driven intracellular magnesium ion (Mg 2+ ) regulation strategy is proposed to reverse drug resistance through constructing Mg 2+ ‐ and doxorubicin (DOX, as model drug)‐loaded bimetallic Pd@Pt nanostructure (DPd@PtM). Although DPd@PtM can deliver Mg 2+ into tumor cells through endocytosis, large amount of Mg 2+ releases outside cells. To this end, the photothermal effect of Pd@Pt nanostructure in the second near‐infrared region is expected to activate the thermosensitive transient receptor potential cation channel subfamily V member 1 (TRPV1) channel for extracellular released Mg 2+ influx. Intercellular Mg 2+ accumulation suppresses tricarboxylic acid cycle to block intracellular adenosine triphosphate (ATP) production (cutoff energy supply for P‐gp) and reduce O 2 consumption (downregulate P‐gp expression), then inhibiting P‐gp‐mediated tumor MDR. Both in vitro and in vivo results demonstrate that DPd@PtM can open TRPV1 channel to elevate Mg 2+ level and then inhibit the P‐gp activity to enhance intracellular DOX concentration for chemotherapy. It is believed that this photothermal‐mediated tumor Mg 2+ regulation therapy based on reversing MDR is a promising strategy to kill cancer cells.