- Publication: Matilde Durán-Lobato, Sulay Tovar, Juan Cuñarro, Rocío Ramos-Membrive, Iván Peñuelas, Ilaria Marigo, Federico Benetti, Miguel Chenlo, Clara V. Álvarez, Vashegyi Ildikó, Rudolf Urbanics, János Szebeni, María José Alonso, Bioinspired orthogonal-shaped protein–biometal nanocrystals enable oral protein absorption, Journal of Controlled Release, Volume 377, 2025, Pages 17-36, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2024.11.016
Highlights:
• Ultrasmall insulin-Zn orthogonal-shaped nanocrystals can be customizably produced.
• A bilayer envelop mimicking cell membranes provides improved nanoparticle stability.
• Preliminary studies suggest scalability and translability to other biomolecules.
• The nanocrystals elicit hypoglycemia in vivo without carrier systemic absorption.
• A final oral capsule elicits over 20 % absolute bioavailabity in healthy awake pigs.
Abstract:
With the growing number of marketed biological drugs, the development of technological strategies for their oral systemic absorption, becomes increasingly important. The harsh gastrointestinal environment and low permeability of the intestinal epithelium, represent a huge challenge for their systemic delivery. Herein, bioinspired in the physiological insulin-Zn interaction, the design of orthogonal-shaped protein-biometal hybrid nanocrystals, further enveloped by a bilayer of functional biomaterials, is reported. The nanocrystals exhibited a size of 80 nm, a neutral surface charge and a high insulin loading. In vitro studies showed the capacity of the nanocomplexes to control the release of the associated insulin, while preserving its stability. In vivo evaluation showed sustained blood glucose reductions in both healthy and diabetic rats (up to 40 % and 80 %, respectively), while chronic immunotoxicity studies in mice indicated no toxicity effect. Preliminary efficacy studies in healthy awake pigs following oral capsule administration showed over 20 % absolute bioavailability.
