Physiological dynamic stretching selectively disrupts pathological AGE crosslinks in porous lung tissue through an architecture-dependent mechanism, enabling mechanotherapy that reverses established pulmonary fibrosis by breaking the mechanobiological feedback loop between matrix stiffening and fibroblast activation, with therapeutic efficacy amplified when combined with pharmacological AGE inhibition.

Extracellular matrix (ECM) stiffness drives cell fate, but tissues are nonlinear and difficult to modify chemically without harming patients. Here, we show that nonlinear mechanical responses of fibrous and porous tissues can be controlled by mechanically modulating crosslinks. Through integrated in vivo, in vitro, and computational approaches, we found that physiological dynamic stretching disrupts pathological advanced glycation end-product (AGE) crosslink-induced fibrogenesis in an architecture-dependent manner. This was effective in lung-like porous scaffolds but not in liver-like fibrous matrices, revealing a critical structure-property relationship. Computational and in vitro models established that this modulates cell-ECM feedback, and that controlling mechanical crosslinking modulates key nonlinearity of networked solids. This discovery inspired a non-invasive, “mechanotherapuetic” ventilation protocol, which reversed pulmonary fibrosis in mice by physically disrupting ECM pathological crosslinks. The therapeutic efficacy was further amplified when combined with pharmacological AGE inhibition. These findings establish design principles for dynamically reprogrammable biological materials and mechano-targeted therapies.