Mechanochemically Coupled Multidimensional Modulation of Calcium Overload

Disruption of calcium ion (Ca 2+ ) homeostasis has emerged as a promising strategy for tumor therapy. However, the intricate regulation of Ca 2+ signaling and the limitations of single-dimensional modulation often hinder therapeutic efficacy. Here, we developed a Janus nanomotor platform that orchestrates mechanochemically coupled multidimensional modulation of Ca 2+ overload for enhanced tumor therapy. Utilizing a liquid–nano–liquid interface-mediated anisotropic encapsulation strategy, amorphous calcium carbonate (ACC) nanoparticles were asymmetrically coated with mesoporous polydopamine (mPDA) and subsequently functionalized with l -arginine ( l -Arg) and hyaluronic acid (HA), forming the Janus ACC@SiO 2 &mPDA-Arg-HA nanomotors that combine structural asymmetry, NO-driven propulsion, and tumor-targeting capability. Within the tumor microenvironment (TME), degradation of the ACC provided a sustained exogenous Ca 2+ reservoir. Simultaneously, the endogenous catalytic conversion of l -Arg into NO triggered self-propulsion, mechanically stimulating the cell membrane to activate Piezo1 channels and promote extracellular Ca 2+ influx. In parallel, NO acted as a gaseous chemical messenger to trigger ryanodine receptors (RyRs)-mediated Ca 2+ release from the endoplasmic reticulum (ER). The mechanically and chemically coupled regulation induces persistent Ca 2+ overload, leading to mitochondrial dysfunction and apoptosis. Our study presents a paradigm of mechanochemical coupling for multidimensional signal modulation, offering a framework for engineering nanomachines that reprogram intracellular signaling in cancer therapy.