Active Soft Hydrogels Reveal Cumulative Molecular Force Dosing in Stem Cell Fate Programming

ABSTRACT Decoupling molecular‐scale mechanical signaling from bulk substrate stiffness remains a fundamental challenge in biomaterial design. Here, we develop a soft‐yet‐active hyaluronic acid hydrogel (∼3 kPa) grafted with near‐infrared‐driven CD‐PNIPAM‐RGD molecular actuators to apply programmable, piconewton‐scale forces directly to integrins without altering the bulk modulus. By isolating force history as an independent variable, we reveal that human mesenchymal stem cells act as cumulative mechanical integrators. A cumulative force dose of just 7 h (1‐h daily pulses) drives irreversible osteogenic commitment on this classically non‐permissive substrate. Mechanistically, each pulse bypasses canonical tension‐based signaling. Despite negligible cytoplasmic traction, localized molecular pulling drives G‐actin nuclear import, intranuclear F‐actin polymerization, and rapid YAP activation. By recasting mechanotransduction from a continuous analog response into a discrete, cumulative integration of mechanical inputs, this work establishes active force dosing as a quantitative design principle for next‐generation soft biomaterials.