A shikonin/Cu2+ coordination complex-encapsulated hydrogel drug depot alleviates myocardial ischemia-reperfusion injury by disrupting energy metabolism-mediated intercellular crosstalk.

In the pathological progression of myocardial ischemia-reperfusion injury (MI/RI), M1 macrophages and hyperactivated cardiac fibroblasts (CFs) synergistically drive tissue damage through metabolic reprogramming-mediated inflammatory storms and fibrotic remodeling. However, addressing the challenge of influencing the interactions between macrophages and CFs through energy metabolism intervention remains a significant therapeutic hurdle. Herein, we developed an innovative hydrogel-based drug depot (pH-SC@ZIF-8) by incorporating hyaluronic acid (HA)-modified zeolitic imidazolate framework-8 (ZIF-8) nanoparticles, which are loaded with shikonin/Cu2+ metal-drug coordination complexes (SC), into a thermosensitive Pluronic F-127 hydrogel. In vitro studies have shown that HA modification enhances the targeting efficiency of nanoparticles toward M1 macrophages and activated CFs, facilitating the accumulation of shikonin and Cu2+ in target cells. This process inhibits glycolysis and activates cuproptosis, leading to a significant reduction in the secretion of inflammatory cytokines (TNF-α, IL-1β) and inducing CF death. In vivo results indicate that the thermos-responsive gelation of the hydrogel facilitates stable and sustained drug release, effectively reducing the inflammatory response at the injury site while exhibiting anti-fibrotic effects. Our study offers a novel therapeutic strategy for cardiovascular diseases by inhibiting energy metabolism to modulate the interactions between immune and tissue cells.