Recursive feedback between Piezo1 conformation and membrane mechanics drives self-organization into finite clusters.

Piezo1 is a major mechanosensitive ion channel through which cells convert physical force into calcium-dependent signaling programs. In living membranes, this conversion depends not only on channel activation, but also on whether Piezo1 channels remain dispersed, assemble into finite clusters, or concentrate at sites where receptor signaling and mechanical forces reorganize the membrane. How single-channel force sensing is amplified into these collective spatial states remains unknown. Here we identify a membrane-feedback mechanism that converts single-channel mechanosensing into self-organized Piezo1 clusters. Coupling channel shape to membrane-cortex elasticity reveals that neighboring channels relax shared deformation fields, generating an effective interaction with short-range attraction opposed by longer-range repulsion. As channel density or membrane tension increases, this balanced interaction shifts Piezo1 from dispersed channels into mesoscale finite clusters. Brownian-dynamics simulations reproduce experimentally observed Piezo1 cluster geometries and swelling-induced cluster growth, while comparisons across distinct cellular systems place Piezo1 organization within a common density-tension framework. Applying the same mechanism to LPS-activated macrophages shows how receptor-induced membrane reorganization locally concentrates Piezo1 above the clustering threshold. Overall, these results recast Piezo1 mechanotransduction from isolated-channel force sensing to a membrane-driven self-organization process that spatially biases force-dependent calcium signaling within cells.