Abstract
<jats:p>Supramolecular hydrogels based on heterochiral tripeptides are suited for biomedical applications, particularly as drug delivery platforms for small-molecule therapeutics that do not disrupt the self-assembly process. The chemotherapeutic drug 5-fluorouracil (5-FU) is widely used in the treatment of gastrointestinal cancers (i.e., hepatocellular carcinoma). However, its clinical utility is limited by systemic toxicity. Redox-triggered drug release, using disulfide linkers, represents a viable strategy to enhance therapeutic efficacy. Here, 5-FU is 2 covalently conjugated to heterochiral tripeptide DLeu–Phe–Phe (lFF) through a disulfidecontaining linker to afford a redox-responsive prodrug hydrogelator. The resulting 5-FU–SS–lFF conjugate retains its ability to form supramolecular hydrogels with viscoelastic properties comparable to those of native lFF hydrogels. Under reducing conditions, disulfide bonds are cleaved, enabling controlled release of 5-FU. Importantly, 5-FU–SS–lFF exhibits anticancer activity in hepatocellular carcinoma spheroids. This work advances heterochiral peptide-based supramolecular hydrogels as versatile and responsive platforms for controlled drug delivery.</jats:p>