Nanotechnology-Fortified Manipulation of Cell Ca²⁺ Signaling

The manipulation of cytosolic Ca²⁺ concentration ([Ca²⁺]_i) plays a crucial role in the study of Ca²⁺ signaling and the therapy of its affected diseases. Nanotechnology enables the development of nanotransducers for targeted, non-invasive, highly spatiotemporal, and on-demand [Ca²⁺]_i regulation by responding to external energy fields to activate Ca²⁺ channels, in situ deliver Ca²⁺, or release the payload of chemical modulators. As considerable strides have been made in Ca²⁺ signaling-related fundamental research and applications in recent years, in this article, it is tried to present a thorough review of nanotransducer-based [Ca²⁺]_i manipulation, from the working principle to specific applications. Focusing on the design rationale and constructions of nanotransducers, the interactions between nanotransducers and Ca²⁺ channels are highlighted, as well as the downstream effectors of Ca²⁺ signaling pathways, followed by their representative biomedical applications in disease treatment and neuromodulation. Moreover, despite the enormous progress made to date, nanotransducer-regulated Ca²⁺ signaling still confronts obstacles, and several scientific issues urgently need to be resolved. Thus, to provide brief and valid instructions for the development of nanotransducers for the regulation of Ca²⁺ signaling, proposals on how to improve the nanotransducer-based [Ca²⁺]_i manipulation as well as future challenges and prospects are discussed.