Ultrasonic-activated La0.93MnO3-mediated super calcium storm induces mitochondrial dysfunction and PANoptosis

A promising strategy for improving calcium-based therapy efficacy involves precisely circumventing off-target toxicity, directly intensifying calcium storm, amplifying immune responses, and minimizing hypercalcemia risk. Inspired by the unique lanthanide contraction and the profound (≈ 15,000-fold) extracellular-to-intracellular Ca 2+ gradient, we developed an ultrasonic-activated lanthanide perovskite ion interferent, polyvinylpyrrolidone-modified La 0.93 MnO 3 (LMOP), to regulate calcium homeostasis. Upon ultrasound (US) irradiation, LMOP releases La 3+ on demand, inhibits calcium-ATPase activity, impeding calcium efflux and endoplasmic reticulum calcium reuptake, while simultaneously hyperactivating mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium influx. Notably, concurrent reactive oxygen species (ROS) generation under US further activates the transient receptor potential ankyrin 1 (TRPA1) channel on the plasma membrane, promoting the influx of extracellular calcium reservoirs and exacerbating intracellular calcium overload. Moreover, ROS and calcium dysregulation directly cause irreversible mitochondrial dysfunction, triggering PANoptosis and immune activation. This US-triggered lanthanide-based strategy offers a precise paradigm for regulating calcium homeostasis, substantially improving the efficacy of calcium interference therapy. Herein, we developed an ultrasonic-activated lanthanide perovskite ion interferent La 0.93 MnO 3 . Upon ultrasound irradiation, it releases reactive oxygen species and La 3+ on demand to enhance Ca 2+ influx and blocking Ca 2+ efflux, funneling the excess Ca 2+ into mitochondria, orchestrating a tumor-specific “super calcium storm”, that cascadingly initiated PANoptosis and immunogenic cell death. Bingbing Duan is a 3 rd year master's degree student at Shanghai University of Engineering Science. Yu Luo (BRID: 05895.00.05880) is a professor at the Institute of Pharmaceutical Frontiers, Shanghai University of Engineering Science. He primarily focuses on the key scientific issue of early diagnosis and efficient treatment of cancer. A total of more than 70 SCI papers have been published, with a total citation frequency of over 5,100 times and H-index of 40. Five papers have been selected as ESI global 1% highly cited papers, and 11 invention patents have been authorized. He has presided over five national and provincial-level projects, and selected as a Shanghai Shuguang Scholar in 2022.