The research and treatment of major diseases challenge global public health, necessitating advanced disease models. Existing approaches have clear limitations: two-dimensional cell cultures lack multi-organ interactions, clinical trials are costly and ethically constrained, and animal models, focused on single organs, fail to replicate systemic regulation. Parabiosis, which connects two organisms via shared circulation, provides insights into systemic factors and multi-organ interactions but has limited applicability to humans. Furthermore, organoids are three-dimensional structures formed through stem cell self-organization that replicate the functions of individual tissues and advance personalized medicine; however, they cannot model inter-tissue interactions. Assembloids overcome these constraints by integrating diverse organoids, enabling sophisticated simulation of multi-organ dynamics. The integration of these parabiosis, assembloids, organoids (PAO) models with emerging technologies, such as artificial intelligence for precision analytics, CRISPR-based gene editing for disease mechanism elucidation, organ-on-a-chip platforms for dynamic environmental control, and soft robotics for replicating physiological biomechanics, promises to revolutionize disease modeling, regenerative medicine, and precision therapeutics. This review evaluates parabiosis, assembloids, and organoids, highlighting their development, current limitations, and transformative potential when combined with frontier biomedical engineering approaches to address complex human diseases.
