Mechanochemically Coupled Multidimensional Modulation of Calcium Overload

Disruption of calcium ion (Ca²⁺) homeostasis has emerged as a promising strategy for tumor therapy. However, the intricate regulation of Ca²⁺ 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 Ca²⁺ 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@SiO₂&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 Ca²⁺ 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 Ca²⁺ influx. In parallel, NO acted as a gaseous chemical messenger to trigger ryanodine receptors (RyRs)-mediated Ca²⁺ release from the endoplasmic reticulum (ER). The mechanically and chemically coupled regulation induces persistent Ca²⁺ 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.