Ultrasonic-activated La_0.93MnO₃-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 Ca²⁺ gradient, we developed an ultrasonic-activated lanthanide perovskite ion interferent, polyvinylpyrrolidone-modified La_0.93MnO₃ (LMOP), to regulate calcium homeostasis. Upon ultrasound (US) irradiation, LMOP releases La³⁺ on demand and 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.