Chirality Bias Tissue Homeostasis by Manipulating Immunological Response

Abstract The physiological chirality of extracellular environments is substantially affected by pathological diseases. However, how this stereochemical variation drives host immunity remains poorly understood. Here, it is reported that pathology‐mimetic M‐nanofibrils—but not physiology‐mimetic P‐nanofibrils—act as a defense mechanism that helps to restore tissue homeostasis by manipulating immunological response. Quantitative multi‐omics in vivo and in vitro shows that M‐nanofibrils significantly inhibit inflammation and promote tissue regeneration by upregulating M2 macrophage polarization and downstream immune signaling compared with P‐nanofibrils. Molecular analysis and theoretical simulation demonstrate that M‐chirality displays higher stereo‐affinity to cellular binding, which induces higher cellular contractile stress and activates mechanosensitive ion channel PIEZOl to conduct Ca 2+ influx. In turn, the nuclear transfer of STAT is biased by Ca 2+ influx to promote M2 polarization. These findings underscore the structural mechanisms of disease, providing design basis for immunotherapy with bionic functional materials.