Flexible liver organoid-based assessment of metal–organic framework biocompatibility toward programmable organoid bioengineering

Metal–organic frameworks (MOFs) are emerging as versatile nanomaterials for biomedical applications owing to their high surface area, tunable porosity, and structural flexibility. However, concerns regarding their biocompatibility and hepatotoxicity, particularly as applications expand from drug delivery toward emerging bioengineering systems, necessitate physiologically relevant platforms for nanotoxicity evaluation. Here, we establish a liver organoid platform for controlled assessment of MOF biocompatibility. Liver organoids derived from hepatic progenitor cells exhibited hepatic characteristics, including hepatocyte marker expression and robust metabolic activity. Using this platform, we systematically evaluated zeolitic imidazolate framework-8 (ZIF-8), one of the most extensively studied MOFs for drug delivery, under defined exposure conditions using a Matrigel-embedded approach across multiple concentration gradients. Across tested concentrations, ZIF-8 caused no detectable changes in organoid morphology and viability. Histological architecture and hepatic function at representative concentrations were confirmed by hematoxylin and eosin staining, and alanine aminotransferase, aspartate aminotransferase, urea, and albumin analyses. Collectively, these findings demonstrate no detectable toxicity at concentrations up to 300 μg/mL under the investigated conditions over 96 h in a physiologically relevant organoid model. Importantly, this proof-of-concept study demonstrates the feasibility of using liver organoids as physiologically relevant platforms for ZIF-8 biocompatibility assessment, supporting multimodal functional readouts and controlled exposure conditions. The proposed organoid-based framework may be extended to systematic evaluation of additional MOF systems with diverse physicochemical properties, compositions, and biomedical applications, while facilitating future exploration of MOFs as programmable nano–bio interfaces for organoid and organoid-on-chips bioengineering. The platform may also support future integration with biosensing, artificial intelligence, and closed-loop bioengineering applications.