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The primary impetus of therapeutic cell encapsulation in the past several decades has been to broaden the options for donor cell sources by countering against immune-mediated rejection. However, another significant advantage of encapsulation is to provide donor cells with physiologically relevant cues that become compromised in disease. The advances in biomaterial design have led to the fundamental insight that cells sense and respond to various signals encoded in materials, ranging from biochemical to mechanical cues. The biomaterial design for cell encapsulation is becoming more sophisticated in controlling specific aspects of cellular phenotypes and more precise down to the single cell level. This recent progress offers a paradigm shift by designing single cell-encapsulating materials with predefined cues to precisely control donor cells after transplantation. 

Abstract The innate immune system plays a dual role in both mediating pathogenic processes following tissue damage and acting as a barrier to effective therapeutic delivery. Strategies that evade immune clearance while modulating host immune components offer promising solutions for treating complex chronic diseases, such as fibrosis. Here, an innate immune checkpoint material‐based strategy is presented in which mesenchymal stromal cells, coated with a soft conformal microgel and functionalized with the CD47 self‐marker agonist, effectively evade clearance by tissue resident macrophages. These engineered cells reverse persistent fibrotic damage in the lungs through a paracrine mechanism. Single‐cell RNA sequencing identifies a transitional antigen‐presenting macrophage subpopulation that mediates these reparative effects. By combining immune cloaking with the presentation of local signals encoded in the gel coatings, this strategy can be used to design secretory cells for long‐term tissue remodeling, enabling a living pharmacy for chronic tissue damage. 

Abstract Various signals in tissue microenvironments are often unevenly distributed around cells. Cellular responses to asymmetric cell‐matrix adhesion in a 3D space remain generally unclear and are to be studied at the single‐cell resolution. Here, the authors developed a droplet‐based microfluidic approach to manufacture a pure population of single cells in a microscale layer of compartmentalized 3D hydrogel matrices with a tunable spatial presentation of ligands at the subcellular level. Cells elongate with an asymmetric presentation of the integrin adhesion ligand Arg‐Gly‐Asp (RGD), while cells expand isotropically with a symmetric presentation of RGD. Membrane tension is higher on the side of single cells interacting with RGD than on the side without RGD. Finite element analysis shows that a non‐uniform isotropic cell volume expansion model is sufficient to recapitulate the experimental results. At a longer timescale, asymmetric ligand presentation commits mesenchymal stem cells to the osteogenic lineage. Cdc42 is an essential mediator of cell polarization and lineage specification in response to asymmetric cell‐matrix adhesion. This study highlights the utility of precisely controlling 3D ligand presentation around single cells to direct cell polarity for regenerative engineering and medicine.