Multiscale Profiling of Nanoscale Metal‐Organic Framework Biocompatibility and Immune Interactions
Yunhui Zhuang, Bárbara B. Mendes, Dhruv Menon, Jhenifer Oliveira, Xu Chen, Fatma Demir Duman, João Conniot, Sergio Mercado Argandona, Xiewen Liu, Shi‐Yuan Zhang, João Conde, Rachel E. Hewitt, David Fairen‐Jiménez
Abstract
Abstract The clinical translation of metal‐organic frameworks (MOFs) – a promising class of porous materials for nanomedicine – is hindered by a poor understanding of their complex interactions with the immune system and in vivo immunotoxicity. To address this gap, a hierarchical “Safety‐by‐Design” pipeline is established and validated, integrating machine learning (ML) with ex vivo human blood studies and targeted in vivo models. This multi‐stage workflow enables the systematic profiling of MOF immunotoxicity, de‐risking their development. The power of this approach is demonstrated using four clinically relevant MOFs – NU‐901, PCN‐222, UiO‐66, and ZIF‐8 – revealing distinct, framework‐dependent immune fingerprints. The initial in silico screening correctly flagged NU‐901 and ZIF‐8 as potential hazards to human health. These predictions are subsequently validated ex vivo, where NU‐901 is confirmed to be selectively cytotoxic to CD14 + monocytes, and ZIF‐8 is identified as a specific pro‐inflammatory agent via IL‐6 induction. In contrast, candidates predicted to be safe – UiO‐66 and PCN‐222 – demonstrated high biocompatibility ex vivo and advanced to in vivo studies, where they caused only minimal and transient immune activation. This study provides a validated, resource‐efficient roadmap for preclinical immunotoxicity assessment, establishing a rational paradigm to accelerate the safe clinical translation of MOFs and other advanced nanomedicines.