Multifunctional Supramolecular Filament Hydrogel Boosts Anti‐Inflammatory Efficacy In Vitro and In Vivo

Peptide‐drug conjugates (PDCs) are an important class of therapeutic agents that combine one or more active molecules with a short peptide via a biodegradable spacer to generate prodrugs. Here an antioxidant (i.e., 3,5‐dihydroxybenzoic acid), a non‐steroidal anti‐inflammatory drug (i.e., ibuprofen, IPF), and a self‐assembled peptide motif (i.e., Gly‐Phe‐Phe‐Tyr‐Asp, GFFYD) are integrated to produce a peptide‐drug amphiphile, which self‐assembles to form hydrogel and further exerts the synergistic effects, and consequently emerges high therapeutic efficacy. In the in vitro study toward lipopolysaccharide‐activated RAW264.7 macrophages, the resulting hydrogel significantly reduces the production of cytokines (e.g., IL‐1β, IL‐6 and tumor necrosis factor‐α (i.e., TNF‐α)) compared with that of native IPF via the inhibition of nuclear factor‐κB (i.e., NF‐κB), janus kinase‐signal transducer and activator of transcription (i.e., JAK‐STAT) signals and NLR family pyrin domain containing 3 (i.e., NLRP3) inflammasome activation. Moreover, a rabbit model of endotoxin induced uveitis evidences the superior therapeutic efficacy of the resulting hydrogel over that of clinically used 0.1 wt% diclofenac sodium eyedrop. Overall, this work offers new insights into the anti‐inflammatory mechanism of PDCs hydrogel and presents the therapeutic values in the treatment of ocular disorders, and ultimately fulfils the potential clinical benefits of PDCs. This work reports a strategy of peptide‐drug conjugate based supramolecular hydrogel which specifically improves the pharmacological activities of therapeutic agents as well as minimizes side‐effects for boosting the anti‐inflammatory efficacy with synergistic effects in vitro and in vivo.