Supramolecular recognition-based hydrogels incorporating vascular endothelial growth factor and hesperadin for...

Myocardial infarction (MI) induces pathological remodeling that drives heart failure. Dual-targeted approaches addressing myocardial repair and angiogenesis are crucial for improving post-infarct prognosis. Previous research has demonstrated that hesperadin (Hes), a CaMKII inhibitor, exhibits anti-apoptotic activity, while vascular endothelial growth factor (VEGF) enhances angiogenesis following infarction. Although these two drugs may hold potential for combination therapy, their co-delivery is compromised by opposing physicochemical properties: Hes is highly hydrophobic, whereas VEGF is hydrophilic and can cause significant adverse effects when administered systemically. Here, we report a supramolecular hydrogel (SHV gel) constructed from hyaluronic acid (HA) and cucurbit[7]uril (CB[7]) to enable synchronized and sustained co-delivery of Hes and VEGF. CB[7] encapsulates Hes through host-guest recognition, thereby enhancing drug dispersibility and loading, while HA confines VEGF to preserve its bioactivity and prolong its release. In vitro and in vivo data reveal that SHV hydrogels combine favorable biocompatibility with sustained co-release of Hes and VEGF, showing superior synergistic efficacy against MI through anti-apoptosis, promoting angiogenesis, inhibiting myocardial remodeling and improving cardiac function compared to mono-component hydrogels. This supramolecular platform represents a promising multifunctional therapeutic strategy for precise MI intervention and clinical translation. STATEMENT OF SIGNIFICANCE: Myocardial infarction (MI) often progresses to heart failure because injured heart muscle dies and blood supply remains insufficient. Combining anti-apoptotic and pro-angiogenic therapies could improve recovery, but co-delivering a hydrophobic small molecule and a fragile, hydrophilic protein in one formulation is difficult, and systemic administration of vascular endothelial growth factor (VEGF) can cause adverse side effects. Here, we develop an injectable supramolecular hydrogel (SHV gel) built from hyaluronic acid and cucurbit[7]uril to synchronize delivery of hesperadin and VEGF. Cucurbit[7]uril encapsulates hesperadin to enhance solubility and loading, while the hyaluronic acid network confines VEGF to preserve bioactivity and prolong release. The resulting hydrogel shows good biocompatibility and synergistically reduces cardiomyocyte apoptosis, promotes angiogenesis, limits remodeling, and improves cardiac function in MI models.