Due to oral degradation in the gut and limited absorption, oral delivery of peptide drugs like semaglutide is challenging. Coacervate-forming polymers offer a potential solution which undergo liquid-liquid phase separation (LLPS) to trap drug molecules. In this study, five acrylamide-based copolymers (Poly1-Poly5) with three replicate simulations per polymer were tested as coacervate carriers for semaglutide using Martini 3 coarsegrained molecular dynamics simulations in GROMACS for 1 µs each. Using parameters like condensation fraction (CF), encapsulation efficiency (EE%), polymer-peptide interaction energy, and peptide diffusion coefficient (D), the performance of the five copolymers was assessed. All five copolymers formed coacervates (CF = 0.54-0.80), but CF alone did not predict the encapsulation performance. Out of them, Poly1 achieved the highest EE% (7.02 ± 0.49%) with strongest interaction energy (-2606 kJ/mol), primarily due to van der Waals contacts. However, Poly5 showed the most consistent peptide mobility suppression. These results demonstrate that polymer-peptide interaction provide more meaningful insight for encapsulation performance than condensation fraction alone.  

Comparison with calcein leakage experiment revealed that Poly1 caused negligible membrane disruption whereas Poly2 induced 70% leakage, indicating that encapsulation efficiency and membrane permeability activity are structurally different and must be optimised separately.