Non‐Contact Transspatial Regulatory Function of the Extracellular Matrix

ABSTRACT As a crucial biological material, the extracellular matrix (ECM) constitutes a major part of the extracellular microenvironment, offering both structural support and essential biological signals to surrounding cells. Research into ECM properties not only deepens our understanding of cellular behavior and metabolism but also opens new avenues for studying disease mechanisms and therapies. In this work, we report a previously unrecognized function of ECM by leveraging a three‐dimensional spatial cavity structure. It is termed “Non‐contact Transspatial Regulatory” (nCTR), referring to the ECM that remotely regulates cells without traditional direct physical contact. Systematic investigation and validation of key factors reveal that nCTR strongly depends on the 3D spatial distance between ECM and cells, governed by both physical spatial confinement and chemical signaling exchange. The process involves multiple components, pathways, and mechanisms, with macropinocytosis playing a dominant role. This newly identified function of the ECM offers a fresh perspective on cellular behavior and will undoubtedly open a new frontier in the cellular microenvironment studies.