Reconstructing the Islets: Advances in 3D Pancreatic Organoid Models for Functional β-Cell Replacement

Pancreatic β-cell replacement represents a promising therapeutic avenue for insulin-dependent diabetes, yet clinical translation has been limited by donor scarcity, immune rejection, and incomplete engraftment. Three-dimensional (3D) pancreatic organoids derived from human pluripotent stem cells (hPSCs) or primary tissue offer a scalable and physiologically relevant platform, recapitulating native islet architecture, paracrine interactions, and glucose-responsive insulin secretion. Recent advances in differentiation protocols, vascularization strategies, and immune-protective approaches—including encapsulation and hypoimmunogenic engineering—have enhanced β-cell maturation, survival, and functional performance in vitro and in vivo. Despite these developments, challenges remain in achieving fully mature β-cells, durable graft function, and scalable, reproducible production that is suitable for clinical use. This review highlights the promise of pancreatic organoid engineering, emphasizing strategies to optimize β-cell maturation, vascular integration, and immune protection, and outlines key future directions to advance organoid-based β-cell replacement toward safe, effective, and personalized diabetes therapies.