López Estévez, Ana MaríaGonzález Portela, MaríaPiñeiro Alonso, LauraGómez Lado, NoemíFraga Codesido, JessicaGarcía Otero, XurxoAguiar Fernández, PabloAlonso Fernández, María José2026-04-232026-04-232026-01-10López-Estévez, A. M., Portela, M. G., Piñeiro-Alonso, L., Castillo-González, R., Sancho-Temiño, L., Gómez-Lado, N., Codesido, J., García-Otero, X., Medel, M., Vicent, M. J., Castellanos, M., Aguiar, P., Fernández-Messina, L., Fernández-Aceñero, M. J., Cruz-Adalia, A., & Alonso, M. J. (2026). Nanoassemblies for oral protein delivery — The case of monoclonals for inflammatory bowel disease. Journal of Controlled Release, 389, 114455. 10.1016/j.jconrel.2025.114455https://hdl.handle.net/10347/46928Biological drugs such as monoclonal antibodies (mAbs) or peptides are the preferred therapeutic approach for the treatment of chronic diseases such as inflammatory bowel disease (IBD) or diabetes. Unfortunately, the necessity of their parenteral administration and poor access to their targets have limited their full exploitation. Nanotechnology has been explored for the oral administration of biologicals, however, the nanocarriers reported so far have shown limited translational value. The objective of this work has been to design a new nanocarrier for the oral administration of therapeutic proteins with a translational potential. We chose as cargos, insulin and two clinically relevant mAbs, Bevacizumab (BVZ, anti-VEGF-A mAb) and Adalimumab (anti-Tumor Necrosis Factor (TNF) mAb). These macromolecules were assembled with amphiphilic biodegradable polymers, either positively charged (based on octaarginine-lauric r8C12) or negatively charged (polyglutamic acid derivatized with myristic acid, PGAC14) with the intention to assess their potential to facilitate the targeted delivery of the selected proteins. After a screening of a library of compositions, nanoformulations named as nanoassemblies (NAs) exhibiting singular features were selected, namely (i) a ultra-small and unimodal size of 50 nm and negative to neutral surface charge, (ii) a high drug loading capacity (>10 %, w/w), (iii) the ability to protect the cargo in simulated GI fluids, and (iv) the capacity to interact with the intestinal epithelium. In vivo PET/MRI biodistribution profile indicates that NAs consisting of BVZ-r8C12 are significantly retained in the colon as compared to free BVZ. The biodistribution analysis in a rat colitis model revealed that the inflamed conditions enhanced significantly the retention pattern of the NAs. On the other hand, a specific prototype containing anti-TNF (PEGylated NAs of anti-TNF mAb and PGAC14) were able to reduce the production of pro-inflammatory cytokines and decrease the colonic inflammation. Briefly, we present a new oral protein delivery platform and show the potential of specific prototypes for treating local inflammation in intestinal tissues. We also realize that to assess their potential further we need to fully understand their mechanism of action.eng© 2025 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ).Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Oral peptide/protein deliveryMonoclonal antibodiesInsulinNanoparticlesBiodistributionPET/MRIInflammatory bowel diseasejournal article10.1016/j.jconrel.2025.1144551873-4995open access