Modulating cell surface chemistry through mild reduction reinforces extracellular-to-intracellular transmission forces and mechano-signaling.

Cell surface engineering offers a powerful strategy to modulate cellular behaviors, including adhesion, migration, and differentiation. While cell fate is typically governed by extracellular cues such as matrix ligands, engineered cell surfaces can reshape how these signals are sensed and transduced. Here, we present a facile and robust approach to cell surface engineering via mild chemical reduction. Using tris(2-carboxyethyl)phosphine (TCEP), a gentle reducing agent, we modulated surface-exposed disulfide bonds to induce adhesion-dependent signaling without genetic manipulation. This strategy was applied to preadipocytes to investigate its effects on cell adhesion, mechanotransduction, and adipogenic differentiation. Mild surface reduction induced pronounced morphological changes, including increased spreading, elongation, and cytoskeletal reorganization. Notably, TCEP treatment enhanced focal adhesion kinase (FAK)-associated adhesion and mechanotransductive signaling, accompanied by elevated cell-matrix traction forces, increased intracellular tension, and enhanced cytoskeletal-nuclear force transmission. These multiscale mechanical responses were quantified using traction force microscopy, intracellular force microscopy, and nuclear envelope wrinkling analysis. Functionally, these coordinated mechanobiological changes suppressed adipogenic differentiation, even under adipogenic induction conditions. Taken together, our findings demonstrate that mild chemical reduction of the cell surface modulates adhesion-dependent mechanotransduction through a FAK-centered force-transmission pathway, reinforcing cytoskeletal and nuclear mechanics to inhibit adipogenesis. This work highlights surface redox modulation as a non-genetic strategy to regulate cellular mechanics and lineage commitment.