Pushing the Limits on the Intestinal Crossing of Metal−Organic Frameworks: An Ex Vivo and In Vivo Detailed Study Rojas Macías, Sara Metal-Organic Frameworks Chitosan Intestinal permeability Caenorhabditis elegans Bioavailability Biocompatible nanoscaled metal−organic frameworks (nanoMOFs) have been widely studied as drug delivery systems (DDSs), through different administration routes, with rare examples in the convenient and commonly used oral administration. So far, the main objective of nanoMOFs as oral DDSs was to increase the bioavailability of the cargo, without considering the MOF intestinal crossing with potential advantages (e.g., increasing drug availability, direct transport to systemic circulation). Thus, we propose to address the direct quantification and visualization of MOFs’ intestinal bypass. For that purpose, we select the microporous Fe-based nanoMOF, MIL- 127, exhibiting interesting properties as a nanocarrier (great biocompatibility, large porosity accessible to different drugs, green and multigram scale synthesis, outstanding stability along the gastrointestinal tract). Additionally, the outer surface of MIL-127 was engineered with the biopolymer chitosan (CS@MIL-127) to improve the nanoMOF intestinal permeation. The biocompatibility and intestinal crossing of nanoMOFs is confirmed using a simple and relevant in vivo model, Caenorhabditis elegans; these worms are able to ingest enormous amounts of nanoMOFs (up to 35 g per kg of body weight). Finally, an ex vivo intestinal model (rat) is used to further support the nanoMOFs’ bypass across the intestinal barrier, demonstrating a fast crossing (only 2 h). To the best of our knowledge, this report on the intestinal crossing of intact nanoMOFs sheds light on the safe and efficient application of MOFs as oral DDSs. 2022-07-06T09:41:13Z 2022-07-06T09:41:13Z 2022-03-17 info:eu-repo/semantics/article ACS Nano 2022, 16, 5830−5838. [https://doi.org/10.1021/acsnano.1c10942] http://hdl.handle.net/10481/75845 10.1021/acsnano.1c10942 eng info:eu-repo/grantAgreement/EC/NGEU/102471 http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional American Chemical Society