Mild photothermal activation of TRPV1 pathway for enhanced calcium ion overload therapy of hepatocellular carcinoma

Transient receptor potential vanilloid 1 (TRPV1) pathway can result in the disruption of intracellular calcium ion (Ca2+) homeostasis, but how to effectively control the process of Ca2+ overload needs to be addressed for tumor treatment. Herein, we developed a mild photothermal activation of TRPV1 pathway strategy for enhanced Ca2+ overload therapy of hepatocellular carcinoma, in which the multifunctional nanoparticle (CNQ) loading with CaCO3, a novel polycyclic conjugated small molecule (2Br-NDIA) and quercetin (Qu) as the core for the efficient mild photothermal therapy (PTT). The photothermal property of CNQ can specifically activate the TRPV1 channel, which leads to mitochondrial Ca2+ overloading and the disruption of intracellular Ca2+ homeostasis. This CNQ-mediated activation of the TRPV1 channel by mild PTT provides an emerging paradigm for enhancing mitochondrial Ca2+ overload therapy and dismantling tumor self-defense, safely expanding cancer therapies for highly refractory tumors.