Polydopamine-coated liposomes for oral delivery of tirzepatide: Overcoming gastrointestinal barriers to improve therapeutic efficacy

Tirzepatide (TZP), the first dual GIP/GLP-1 receptor agonist, offers substantial therapeutic benefits for type 2 diabetes mellitus (T2DM) but remains confined to subcutaneous injection. While oral delivery of peptide therapeutics improves patient compliance, it is severely hampered by enzymatic degradation and mucosal barriers in the gastrointestinal tract. Liposomes, as biocompatible nanocarriers, can protect encapsulated drugs, enhance intestinal stability, and enable controlled release. Herein, TZP-loaded liposomes (TZP-Lip) were prepared via reverse-phase evaporation and further coated with polydopamine (PDA) to obtain TZP-Lip@PDA for enhanced oral delivery. TZP-Lip@PDA exhibited an encapsulation efficiency of 95.02 ± 1.14%, a particle size of 145.9 ± 1.49 nm, and preservation of the secondary structure of TZP. The PDA coating functioned as a physical diffusion barrier that conferred sustained-release behavior in simulated gastrointestinal fluids, while enhancing mucus penetration and promoting cellular uptake in Caco-2 cells. Pharmacokinetic studies showed that oral TZP-Lip@PDA achieved measurable plasma exposure, whereas oral free TZP remained below the lower limit of quantification (LLOQ, 5 ng/mL). Despite a tenfold higher dose (8.8 vs 0.88 mg/kg), oral TZP-Lip@PDA achieved a Cmax approximately 50% of that observed after subcutaneous administration of free TZP, within the 12-h sampling window, indicating substantial progress but also the remaining quantitative gap between the two routes. In T2DM rats, oral TZP-Lip@PDA (8.8 mg/kg) significantly enhanced the integrated hypoglycemic response during the 12-h observation period compared with oral free TZP and TZP-Lip. In summary, TZP-Lip@PDA enhances the oral delivery of TZP by sustaining drug release, enhancing mucus penetration and promoting cellular uptake, which offers a potential strategy for peptide and protein oral delivery.