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 (MSN(Ins)) were co-formulated with β-lactoglobulin to prevent premature gastric release, enabling delayed controlled intestinal delivery and protecting insulin from degradation. MSN functionalization with polyethylene glycol and phosphonate groups further enhanced MSN colloidal stability and insulin solubility. Phosphonated MSN, in particular, exhibited efficient interactions with intestinal cells, modulating the reorganization of tight junction proteins to promote the paracellular transport of MSN(Ins). Insulin delivered through these formulations retained its activity, as demonstrated by activation of insulin-responsive signaling pathways in vitro and reduction of blood glucose levels in hyperglycemic mice, hallmark responses of insulin treatment in type 2 diabetes. These findings highlight MSN as promising carriers for oral peptide delivery, supporting the development of effective, patient-friendly therapies with enhanced efficacy and compliance.