Synthetic Cell‐Based Tissues for Bottom‐Up Assembly of Artificial Lymphatic Organs

Synthetic cells have emerged as a novel biomimetic approach for studying fundamental cellular functions and enabling new therapeutic interventions. However, the potential to program synthetic cells into self-organized 3D collectives to replicate the structure and function of tissues has remained largely untapped. Here, self-assembly properties are engineered into synthetic cells to form millimeter-sized 3D lymphatic bottom-up tissues (lymphBUTs) with mechanical adaptability, metabolic activity, and hierarchical microstructural organization. It is demonstrated that primary human immune cells spontaneously infiltrate and functionally integrate into these synthetic lymph nodes to form living tissue hybrids. Applying lymphBUTs, it is shown that structured 3D organization and mechanical support drives T cell activation and the application of lymphBUTs for ex vivo expansion of regulatory CD8⁺ T cells is demonstrated. The study highlights the functional integration of living and non-living matter, advancing synthetic cell engineering toward 3D tissue structures.