Development of 3-carboxypropyl-grafted bio-inorganic lamellar nanocomposite as a new oral delivery platform for therapeutic peptides

• 3-Carboxypropyl-grafted bio-inorganic lamellar nanocomposite (CA-clay) is fabricated as a new tailor-made drug delivery carrier for peptides. • CA-clay is nontoxic and efficiently cleared from the body via the urinary and fecal elimination, displaying the low risk of long-term tissue accumulation. • CA-clay enhances the cellular uptake and thermal stability of peptidyl drugs. • CA-clay has high potential as a biocompatible oral drug delivery carrier for peptides. Introduction: One of the primary challenges in developing peptide drugs lies in their low permeability and inherent instability. Therefore, formulations that stabilize peptides and enhance the membrane transport are crucial for successful product development and improved clinical outcomes. Objectives: This study aims to construct a bio-inorganic lamellar nanocomposite as a new oral delivery platform stably anchoring therapeutic peptides. Results: 3-Carboxypropyl-grafted phyllosilicate (CA-clay) is fabricated via a sol–gel synthesis. CA-clay has layered structures with an interlayer space of approximately 1.72 nm and is dispersed in water as an anionic nanosheet. CA-clay was non-toxic up to 500 μg/mL, with no impact on cell viability, membrane integrity, or apoptotic activity in various cell lines. Furthermore, when administered intravenously or orally to rats, CA-clay is rapidly cleared from the body primarily through urinary and fecal excretion, resulting in almost complete dose recovery within 24 h. These findings suggest that CA-clay is unlikely to persist in tissues, supporting its low potential for long-term accumulation. CA-clay maintains negative charges across a range of acidic to basic pH, forming a stable nanocomplex with peptides having a wide range of isoelectric points. CA-clay-based nanocomplex greatly improves the thermal stability of melittin, a heat-labile peptide, during long-term storage at elevated temperature. Furthermore, CA-clay-based nanocomplex significantly enhances the cellular uptake and the oral efficacy of insulin in diabetic rats. Conclusion: CA-clay has strong potential as a nontoxic, biocompatible drug delivery carrier, paving the way for an efficient oral delivery platform for therapeutic peptides.