Oral administration of peptide-based drugs offers improved patient compliance compared to injectable formulations. However, this route is hindered by several physiological barriers like enzymatic degradation, poor intestinal permeability, and low absorption in the gastrointestinal tract. To address these challenges, a novel virus-mimicking nanocarrier was developed for the oral delivery of liraglutide. Hollow mesoporous silica nanoparticles (HMSN) were synthesized via a co-condensation method and subsequently functionalized with a positively charged cell-penetrating peptide (CPP; KLPVM) to facilitate transcellular transport, and with negatively charged hyaluronic acid (HA) to enhance mucus penetration and enable receptor-mediated targeting. Liraglutide was efficiently encapsulated within HMSN matrix, achieving an encapsulation efficiency of 96.16% and a drug loading of 19.23%. In vitro release studies showed pH-responsive behavior, with limited release under acidic gastric conditions (7%) and sustained release at near-neutral intestinal pH (77% over 12 h). Cellular uptake studies revealed enhanced internalization of the HMSN-CPP@HA (98.1%), predominantly via caveolae-mediated endocytosis. Ex vivo intestinal permeability studies further confirmed improved transmucosal transport, with permeability increasing from 34.4% for MSNs to 97.6% for HMSN-CPP@HA. Pharmacodynamic evaluation in streptozotocin-induced diabetic rat models showed that oral administration of liraglutide-loaded virus-mimicking HMSNs resulted in a 50.98% reduction in fasting blood glucose and a 14.6% decrease in body weight over 28-day period. These outcomes were comparable to those achieved via subcutaneous liraglutide administration (62.7% and 19.2% respectively). These findings suggest that HMSN-CPP@HA preserve the biological activity of liraglutide during gastrointestinal transit, enhance intestinal absorption, and mimic viral translocation mechanisms, representing a promising platform for non-invasive oral delivery of peptide drugs.
