Assembloids: The next frontier in 3D tissue modeling for human biology

For decades, biomedical research has relied on traditional 2D cell cultures and animal models, yet these approaches often fail to capture the intricate cellular interactions that define human physiology. Organoids—self-organizing 3D structures derived from stem cells—have brought researchers closer to replicating organ-specific functions, but they still lack the interconnectivity and multicellular complexity found in vivo. Assembloids overcome this limitation by integrating multiple organoids or diverse cell types, enabling scientists to study large-scale biological phenomena such as neural circuitry formation, gut-brain interactions, and immune-tumor dynamics. This next-generation approach marks a critical step toward more physiologically relevant models for studying human biology.

Published (DOI: 10.26599/CO.2025.9410010) on December 27, 2024, in the journal Cell Organoid, a comprehensive review from researchers at Peking University and Peking University Third Hospital explores the transformative potential of assembloids. The study systematically classifies assembloids into four major categories—multi-region, multi-lineage, multi-gradient, and multi-layer—each tailored to model specific human systems, including the nervous, digestive, urinary, reproductive, and circulatory systems. With their ability to replicate complex biological interactions, assembloids offer unparalleled insights into disease mechanisms and human development, advancing the frontiers of biomedical research.

The review details how different types of assembloids are designed to simulate distinct biological processes. Multi-region assembloids combine organoids from different anatomical areas, enabling the study of inter-regional communication, including the reconstruction of specific neural pathways and the investigation of cell migration dynamics, such as modeling cortical interneuron migration or cancer cell invasion. Multi-lineage assembloids incorporate diverse cell types—such as microglia or endothelial cells—to investigate tissue-tissue interactions, like the neuroimmune axis in neurodegenerative disorders and vascular contributions to organoid maturation. Multi-gradient assembloids employ biochemical gradients to mimic developmental pathways, offering a controlled environment to study morphogen-driven tissue patterning while shedding light on disorders linked to regional specification. Meanwhile, multi-layer assembloids recreate the intricate architecture of hollow organs, such as the gastrointestinal tract, by integrating epithelial and stromal components.

A standout application of assembloids lies in modeling neurodevelopmental disorders, such as Timothy syndrome, where assembloid-based studies have revealed defects in interneuron migration. They have also played a crucial role in infectious disease research, such as modeling SARS-CoV-2 infection in the brain using pericyte-like cells. In oncology, assembloids have demonstrated their potential to replicate tumor microenvironments, providing new insights into the metastasis of small-cell lung cancer to the brain.

"Assembloids represent a significant leap forward in our ability to model human tissues in vitro," says Dr. Kai Wang, co-corresponding author of the study. "By integrating multiple cell types and organoids, we can now study complex interactions that were previously inaccessible, paving the way for more accurate disease modeling and drug discovery."

Looking ahead, assembloids hold immense potential in drug development and personalized medicine. By offering a more physiologically relevant platform, they can enhance drug efficacy and toxicity screening, potentially reducing the reliance on animal models. In parallel, assembloids provide unprecedented insights into neurological disorders, infectious diseases, and cancer, enabling researchers to explore novel therapeutic targets in a controlled environment. Beyond disease modeling, assembloids contribute to developmental biology by improving our understanding of human organogenesis and tissue maturation. With advances in bioengineering, including microfluidic systems, bioprinting, and AI-driven modeling, assembloids are also emerging as scalable platforms for high-throughput drug screening and precision medicine applications. Looking further ahead, their potential extends to regenerative medicine and organ transplantation, where they may facilitate functional tissue replacements and personalized therapeutic strategies.

This work was supported by National Key R&D Program of China (2022YFA1104800), Beijing Natural Science Foundation (JQ23029, L246020, L244089, L234024, L234021), National Natural Science Foundation of China (82370514, 32401144, 82472171), Beijing Nova Program (20220484100, 20230484448), Beijing Municipal Science & Technology Commission (Z231100007223001), the open research fund of State Key Laboratory of Cardiovascular Disease, Fuwai Hospital (2022KF-04), Clinical Medicine Plus X-Young Scholars Project, Peking University (PKU2024LCXQ006), Emerging Engineering Interdisciplinary-Young Scholars Project, Peking University, the Fundamental Research Funds for the Central Universities (PKU2023XGK011), Scientific and Technological Innovation project of China Academy of Chinese Medical Science (C12023C056YLL), the open research fund of State Key Laboratory of Digital Medical Engineering, Southeast University (2023K-01), the open research fund of Beijing Key Laboratory of Metabolic Disorder Related Cardiovascular Disease, Beijing, PR China (DXWL2023-01), the open research fund from State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital (BYSYSZKF2023023). the Innovation and Translation Fund of Peking University Third Hospital (BYSYZHKC2023106) and Elite Support Program (jyzc2024-04).

Author Biography

Professor Kai Wang is an Assistant Professor in the Department of Physiology and Pathophysiology at Peking University, where he also leads a research group as a Principal Investigator at the State Key Laboratory of Vascular Homeostasis and Remodeling. He completed his Ph.D. at Peking University and pursued postdoctoral training at Harvard Medical School/Boston Children’s Hospital and Cornell University from 2016 to 2021. His laboratory specializes in interdisciplinary research on stem cells and vascular organoids. Professor Wang holds editorial roles as an Associate Editor for Microvascular Research and a Co-Editor-in-Chief in Cell Organoid, and serves on the editorial board of Cell Transplantation. He has authored 18 peer-reviewed publications in high-impact scientific journals, including Cell Stem Cell, Science Advances, Advanced Science, Advanced Materials, and Biomaterials. Additionally, he contributes as an ad hoc reviewer for prestigious journals such as Science Advances, ACS Nano, and Angiogenesis.

Dr. Xi Wang is a distinguished Principal Investigator affiliated with the Clinical Stem Cell Research Center of Peking University Third Hospital, the State Key Laboratory for Female Fertility Promotion, and the Institute of Advanced Clinical Medicine at Peking University. Her research primarily centers on unraveling the mechanisms underlying diabetes and reproductive endocrine disorders, as well as developing innovative therapeutic strategies. Dr. Wang earned her Ph.D. from Cornell University in the United States and further honed her expertise through postdoctoral training in the renowned laboratory of Dr. Douglas A. Melton at Harvard University’s Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute. Her scholarly contributions include 32 publications in leading journals such as Cell Stem Cell, Science Translational Medicine, Science Advances, Advanced Materials, and Trends in Cell Biology. In addition to her academic achievements, Dr. Wang is an accomplished innovator, having filed over 10 patents. Among these, she holds 2 PCT international invention patents, 3 US patents, and 5 Chinese patents, underscoring her significant impact on both scientific research and translational medicine.

About Cell Organoid

Cell Organoid aims to provide a worldwide platform for research into all aspects of organoids and their applications in medicine. It is an open access, peer-reviewed journal that publishes high-quality articles dealing with a wide range of basic research, clinical and translational medicine study topics in the field.

Journal website: https://www.sciopen.com/journal/3007-6552

Submission site: https://mc03.manuscriptcentral.com/cellorganoid