Mesoporous Silica Nanoparticles‐Based Formulations for Enhanced Oral Delivery of Peptide Drugs: A Case Study on Insulin

Peptide drugs have revolutionized modern medicine owing to their high potency, selectivity, and excellent tolerability. 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-loaded MSN were co-formulated with succinylated β-lactoglobulin to produce pH-responsive tablets that limited premature gastric release (≤13% after 2 h at pH 1.2) and protected insulin from enzymatic degradation, while enabling controlled intestinal release (up to 88%-98% at pH 7.4). Surface functionalization with polyethylene glycol and phosphonate moieties improved colloidal stability and increased insulin solubility by ∼2.5-fold. The interaction of phosphonated MSN with intestinal epithelial cells further induced transient reorganization of tight junction proteins, enhancing paracellular insulin transport (26% after 24 h, compared with 13% for non-confined insulin). Delivered insulin retained bioactivity, as demonstrated by activation of insulin-responsive 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.