Mechano-immunomodulatory biomaterials: From immune mechanosensing to translational design.

Mechanical cues are increasingly recognized as active regulators of immune-cell behavior rather than passive properties of tissues or biomaterials. In mechano-immunology, matrix stiffness, viscoelasticity, topography, shear stress, tensile strain, compression, and interstitial fluid pressure are understood to shape macrophage polarization, dendritic-cell maturation, neutrophil trafficking, T-cell activation, and tissue repair through coordinated mechanosensing and mechanotransduction. Yet immune responses to mechanical cues remain highly context-dependent, making simplified rules such as "stiff matrices promote inflammation" or "soft matrices promote repair" difficult to generalize across material systems, dimensionalities, ligand-presentation profiles, immune-cell sources, and activation states. Key bottlenecks include reconstructing multidimensional in vivo mechanical microenvironments, standardizing mechanical characterization and reporting, resolving immune-cell heterogeneity, and bridging reductionist platforms with clinically deployable biomaterials. Here, we summarize how immune cells decode mechanical signals through membrane-proximal mechanosensors, cytoskeletal remodeling, nuclear mechanotransduction, epigenetic regulation, and mechano-metabolic coupling. We then discuss how biomaterial parameters, including stiffness, viscoelasticity, mechanical stimulation, surface topography, degradation, and mechano-responsive delivery, can be engineered to modulate immunity in tissue regeneration, drug delivery, and theranostics. Finally, we highlight how artificial intelligence (AI)-enabled biophysical modeling and multimodal data integration may define context-specific mechanical design windows and accelerate next-generation mechano-immunomodulatory biomaterials.