Jiayi Zhang, Jiayi Zhang, Wenfei Xu, Y. Xu, Shuxuan Zhu, Wenjing Liu, Hong Sun, H. Li, Jingfang Zhang, Jingfang Zhang, Zhaogang Sun, Hongqian Chu
ABSTRACT Photothermal therapy (PTT) shows great potential in cancer treatment due to its precise spatiotemporal control, but single‐modal PTT has limitations such as uneven heat distribution and tumor thermotolerance caused by high expression of heat shock protein 90 (HSP90) in cancer cells. Here, a photothermal‐driven nanoplatform (denoted as HCPH) was developed to regulate subcellular calcium ion translocation, induce mitochondrial dysfunction, and enhance PTT efficacy. Specifically, HCPH is based on hollow mesoporous Prussian blue nanoparticles (HMPB NPs), which are loaded with curcumin (CUR) and modified with hyaluronic acid (HA) on their surface. Under near‐infrared (NIR) laser irradiation, it exhibited excellent photothermal conversion efficiency, targeted tumor cells via CD44‐mediated endocytosis, and released CUR under acidic conditions. Notably, CUR induced endoplasmic reticulum (ER) Ca 2 ⁺ release and inhibited HSP90, while the photothermal effect of HCPH activated the TRPV1 calcium channel on the cell membrane to promote Ca 2 ⁺ influx. The dual‐pathway synergy caused cytoplasmic and mitochondrial Ca 2 ⁺ overload, leading to mitochondrial dysfunction and reduced ATP synthesis, which further inhibited HSP90 expression and formed a “PTT‐calcium disorder‐enhanced PTT” cycle. In vitro and in vivo experiments confirm that HCPH significantly improved tumor therapeutic efficacy through photothermal‐driven subcellular calcium translocation regulation and mitochondrial damage.