Cadherin-engineered microspheres enable scalable biofabrication of multilineage liver organoids

Reproducing the spatiotemporally coordinated emergence of vascular, biliary, and parenchymal compartments of the human liver remains a persistent bottleneck in organoid engineering. We introduce biodegradable poly(lactic-co-glycolic acid) microspheres that display epithelial (E) cadherin and vascular endothelial (VE) cadherin fusion proteins and deliver morphogens, mimicking key developmental signals that guide liver organogenesis. When combined with mesenchymal stem cells (MSCs), the microspheres supply adhesion cues that drive aggregate compaction. E-cadherin engagement induces Yes-associated protein activation, priming MSCs for lineage induction. Complementarily, VE-cadherin and vascular endothelial growth factor jointly establish an endothelial niche that delivers inductive cues for hepatic lineage divergence. The resulting organoids display compartmentalized architecture comprising hepatocytes, cholangiocytes, mesenchymal cells, and endothelial networks and respond to hepatotoxic compounds with clinically relevant phenotypes. Unlike induced pluripotent stem cell-based or multiple cell cocultures, this single-source MSC system achieves self-organization through cadherin-defined adhesion and timed morphogen delivery. These elements define a scalable, cadherin-defined biomaterial platform for liver organoid engineering, enabling translational use in drug evaluation and regenerative medicine.