Carrier-Free Self-Assembly of Choline Chloride-Ammonium Glycyrrhizinate Hydrogel for Myocardial Infarction Microenvironment Regulatio

Myocardial infarction (MI)-induced persistent disruption of the myocardial microenvironment is one of the key mechanisms driving the onset of heart failure. Precise modulation of this pathological microenvironment in vitro has emerged as an important strategy to improve MI prognosis and delay heart failure progression. In this study, we constructed carrier-free choline chloride (ChCl)-ammonium glycyrrhizinate (AG) self-assembled hydrogels. Initially, network pharmacology combined with big data analysis was employed to predict the synergistic therapeutic effects of ChCl and AG. Subsequently, multi-scale characterisation techniques, including FT-IR, SEM, and rheology, were used to analyse the structural features of the gel system. Molecular dynamics and quantum chemical calculations indicated that hydrophobic, electrostatic, and hydrogen-bond interactions jointly drive self-assembly, and Cryo-SEM revealed for the first time a near-native interpenetrating sheet-like fibrous network. In an in vitro MI model, the ChCl-AG self-assembled hydrogel reduced oxidative stress, shifted macrophages from pro-inflammatory M1 to reparative M2, increased endogenous antioxidant enzyme activity, and downregulated pro-inflammatory cytokines, thereby preserving microenvironmental homeostasis and providing cardioprotection. Transcriptomics indicated positive regulation of pathways linked to cardiac structure, contractility, energy metabolism, and cardiovascular disease. In vivo MI models, the ChCl-AG self-assembled hydrogel markedly promoted myocardial repair and functional recovery while exhibiting good biocompatibility and sustained release. Overall, the carrier-free ChCl-AG self-assembled hydrogel provides a precise strategy to modulate post-MI inflammatory and oxidative imbalances, promote myocardial repair, and holds broader biomedical potential.