Supramolecular Self-Assembled\nHydrogel for Antiviral\nTherapy through Glycyrrhizic Acid-Enhanced Zinc Absorption and Intracellular\nAccumulation

Respiratory syncytial virus (RSV) is a common pathogen\nthat causes\nrespiratory infections in infants and children worldwide, significantly\nimpacting hospitalization rates in this age group. Zinc ions are considered\nto have broad-spectrum antiviral potential against RNA viruses, including\nRSV. However, poor organism absorption and low intracellular accumulation\nof zinc require repeated high-dose supplementation, which may lead\nto unnecessary toxic side effects. In this research, a Zn<sup>2+</sup>-mediated glycyrrhizinic acid (GA)-based hydrogel (ZnGA Gel) was\nintroduced and potentially developed to be a clinically available\ndrug candidate for RSV therapy. ZnGA Gel was fabricated based on the\ncooperation of two potential RSV inhibiting molecules (Zn<sup>2+</sup> and GA), where Zn<sup>2+</sup> promoted self-assembly of GA and\nreduced its gel concentration and GA promoted zinc absorption and\ndistribution in lung tissue in vivo. The facile construction of supramolecular\nhydrogel by the self-assembled coordination complex made it an injectable,\ntemperature-sensitive, and pH-responsive controlled-release drug delivery\nfor Zn<sup>2+</sup>. Most importantly, GA was observed to enhance\norganism absorption and intracellular accumulation of Zn<sup>2+</sup> and was identified as a zinc ionophore for the first time. GA can\ncolonize on the cell membrane and disturb cell membrane potential,\nresulting in an enhanced cell membrane permeability. In the presence\nof GA, more than 4.7-fold increasing Zn<sup>2+</sup> concentrations\nmaterialized in the intracellular cytoplasm, compared to Zn<sup>2+</sup> alone administration. This intracellular Zn<sup>2+</sup> accumulation\ndirectly boosted the antiviral activities through improved inhibition\nof RSV replication-associated proteins and significantly inhibited\nRSV replication. Oral administration of ZnGA Gel on the RSV-infected\nmice model achieved an ideal therapeutic effect by effectively lowering\nviral load in the lungs, alleviating lung injury symptoms, and reducing\ninflammatory cell infiltration at pathological sites. The mechanism\ninvolved the inhibition of RSV replication-related proteins, aligning\nwith our in vitro results. Additionally, ZnGA Gel had demonstrated\nbiocompatibility, and reasonable supplementation of zinc was acceptable\nand effective for infants and children in clinical practice. Hence,\nthe ZnGA Gel developed by us holds promise as an effective anti-RSV\nmedicine in the future.