Harnessing Physical Signals for Molecular‐Layer Spatiotemporal Control of Cellular Functions

ABSTRACT

Physical signals are integral components of the cellular microenvironment and play pivotal roles in shaping cellular activities and functions. Yet how diverse physical stimuli are sensed, decoded, and integrated at the molecular level into coherent biological outputs remains unclear, and a unified mechanistic framework with a hierarchical classification is still lacking. In this review, we take a molecular‐layer perspective and propose three core modes of physically mediated cellular regulation: direct regulation mediated by changes in protein state, proximal regulation mediated by nucleic‐acid–level changes, and distal regulation mediated by ion‐concentration dynamics. We compare these modes in terms of their sensing mechanisms, spatiotemporal operating ranges, amplification architectures, and reversibility, and show how they complement one another to form a hierarchical, continuous, and highly integrated signaling network that enables cells to respond to complex and dynamic physical microenvironments. Finally, we discuss key translational challenges—including biocompatibility, scalability, and long‐term safety—and outline opportunities for future development in precision medicine, regenerative medicine, and intelligent biomanufacturing systems.