Release Dynamics of Folic Acid from Peptidomimetic Polyesters: A Multi-Scale Investigation from Bulk Properties to Molecular Interactions.

Clinical studies have demonstrated that the daily intake of folic acid can reduce the incidence of neural tube defects (NTDs) by 70%. Despite widespread awareness of the need for folic acid supplementation, certain communities remain at a high risk for NTDs. To overcome these limitations, sustained and controlled delivery systems based on natural and synthetic polymers have been extensively explored. However, these systems often fail to maintain long-term release due to an incomplete understanding of how polymer properties influence drug release kinetics. As a result, achieving long-term control of drug release often requires complex strategies, including polymer blending or coating techniques, complicating both device fabrication and the understanding of release mechanisms. In this work, we present a simple yet effective drug delivery system based on modular peptide-like polyesters, specifically designed for tunable, long-term release of folic acid. The well-defined architecture of these systems allows us to clearly demonstrate, through extensive characterization and simulations, that folic acid release is primarily governed by physical and chemical interactions among key functional groups of the polymer, folic acid, and water.