Piezo1-mediated regulation of macrophage-derived exosome secretion via nanoparticle elasticity for tumor immunomodulation

The role of nanomechanical cues in regulating exosome biogenesis and function is poorly understood. Herein, we engineer silica nanoparticles (SNs) with tunable elasticity (Young's modulus from 103.2 to 1,064.7 MPa) to probe this mechanism. We demonstrate that softer SNs (20% SNs, 103.2 MPa) significantly boost exosome secretion from bone-marrow-derived macrophages (BMDMs). This process is mediated by the activation of the mechanosensitive ion channel Piezo1, subsequent calcium influx, and the Calcium/Calmodulin-dependent Kinase II Alpha (CAMK2A)/guanosine triphosphate (GTP)-Rab8 signaling axis. Proteomic analysis reveals that these "nanomechanically engineered exosomes" (Exo 20% SNs ) are enriched with proteins that coordinately amplify T cell receptor signaling. Consequently, Exo 20% SNs exhibit superior pro-inflammatory capacity and, in a mouse tumor model, effectively suppress tumor growth and remodel the immunosuppressive tumor microenvironment, outperforming exosomes from lipopolysaccharide (LPS)-activated macrophages. This work establishes a paradigm of nanomechanically engineered exosomes, providing a novel strategy for precision immunotherapy.