Matrix Assisted Assembly of Protocells into Multi‐responsive Prototissues for Mechanical and Chemical Communication

Abstract The extracellular matrix (ECM) provides an integrated 3D environment for living cells to communicate and display collective behaviors. In bottom‐up synthetic biology, several new types of synthetic prototissues (assemblies of synthetic protocells) are developed to mimic various aspects of cellular signaling. However, the spatiotemporal interplay between supporting matrix and protocells, which is critical for mimicking macroscopic responsiveness of multicellular organisms, has remained challenging to control. Herein, a modular strategy is reported to construct macroscopic prototissues with complex structures based on hierarchical assembly of matrix and polymeric protocells prepared by using CaCO 3 sacrificial microparticle templates. Mechanical coordination between protocells and matrix allows for the transformation in response to both the presence and history of multiple stimuli. Taking advantage of the multi‐responsiveness, it further demonstrated an artificial form of metabolic behaviors where a digestive prototissue prey on a substrate‐containing prototissue by two‐way communication. Overall, the methodology presents a strategy to achieve mechanical and chemical communication in matrix containing, tissue‐like materials harboring the potential to reconstitute collective behaviors for bottom‐up synthetic biology and bioinspired engineering.