From mechanical cues to remote immune control: mechanotransductive and stimuli-responsive biomaterials for precision immunomodulation

The importance of mechanotransduction as a key regulator of immune-cell function has grown, linking the tissue microenvironment to cell phenotype, activity, and response to therapy. Mechanobiology and stimuli-responsive biomaterials are converging to become a new approach to precision immunomodulation, the focus of this review. The roles of matrix stiffness, viscoelasticity, confinement, and nanoscale topography in sensing by integrins, focal-adhesion complexes, Piezo1, YAP/TAZ and nuclear mechanotransduction by LINC complexes, and their influence on cytoskeletal organization, transcriptional programs, and immune-cell function, are described. We then explore how macrophages, dendritic cells, T cells, neutrophils, monocytes, and regulatory immune cells combine these mechanical signals with biochemical signaling. We focus on stiffness-tunable, stress-relaxing, adaptive, self-healing, and architecture biomaterials, as well as magnetic, electrical, photonic, acoustic, and multi-stimuli-responsive platforms. They are evaluated for therapeutic roles in cancer immunotherapy, chronic inflammation, wound healing, fibrosis, infection and foreign body-associated responses. Lastly, we discuss barriers to translation, including biological heterogeneity, dosimetry, biosafety, manufacturing, and regulatory challenges, as well as new opportunities based on artificial intelligence, digital twins, real-time sensing, and closed-loop control. Together, these advances establish biomaterials as programmable interfaces that can dynamically integrate mechanical and biochemical cues to orchestrate and achieve a spatio-temporally precise immune regulation.