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However, oral delivery remains limited, and most peptide drugs are administered parenterally due to their inherent instability to proteolytic digestion and poor ability to cross gastrointestinal barriers, which hinders efficient absorption into the bloodstream. This study presents a multifunctional oral delivery system based on mesoporous silica nanoparticles (MSN) customized for insulin administration. Insulin\u2010loaded MSN were co\u2010formulated with succinylated \u03b2\u2010lactoglobulin to produce pH\u2010responsive tablets that limited premature gastric release (\u226413% after 2\u00a0h at pH 1.2) and protected insulin from enzymatic degradation, while enabling controlled intestinal release (up to 88%\u201398% at pH 7.4). Surface functionalization with polyethylene glycol and phosphonate moieties improved colloidal stability and increased insulin solubility by \u223c2.5\u2010fold. The interaction of phosphonated MSN with intestinal epithelial cells further induced transient reorganization of tight junction proteins, enhancing paracellular insulin transport (26% after 24\u00a0h, compared with 13% for non\u2010confined insulin). Delivered insulin retained bioactivity, as demonstrated by activation of insulin\u2010responsive signaling pathways in vitro and reduced blood glucose levels in hyperglycemic mice. These results highlight MSN as a promising platform for oral peptide delivery with improved efficacy and patient compliance.<\/jats:p>","DOI":"10.1002\/smll.202513347","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:29:21Z","timestamp":1774247361000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mesoporous Silica Nanoparticles\u2010Based Formulations for Enhanced Oral Delivery of Peptide Drugs: A Case Study on Insulin"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2857-0430","authenticated-orcid":false,"given":"Claudia","family":"Iriarte\u2010Mesa","sequence":"first","affiliation":[{"name":"Department of Functional Materials and Catalysis Faculty of Chemistry University of Vienna  Vienna Austria"},{"name":"Vienna Doctoral School in Chemistry (DoSChem) University of Vienna  Vienna 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