Janus hydrogels delivering low-density lipoprotein receptor-related protein 6 inhibitor enhance myocardial repair via m6A-dependent cuproptosis in bama pigs.

Copper overload induces a unique form of cell death called cuproptosis via mitochondrial ROS accumulation. Following myocardial infarction (MI), copper ion levels rise significantly in infarcted tissue. Cardiomyocytes, highly sensitive to copper, respond through activation and nuclear translocation of LRP6, which interacts with ALKBH5 to suppress m6A modification of ferredoxin 1 (FDX1), thereby exacerbating copper toxicity. LRP6 also facilitates copper influx, further promoting cuproptosis. High-throughput screening identified chrysin-7-O-glucuronide (C7Og) as a potent LRP6 inhibitor that mitigates cuproptosis without compromising cardiac protective effects. Moreover, a Janus hydrogel enhanced with benzalkonium chloride-modified tannic acid improves tissue adhesion and glucose delivery. A myocardial patch integrating C7Og within this hydrogel significantly reduced infarct size and improved cardiac function in both rat and Bama miniature pig models, highlighting strong translational potential for MI therapy. STATEMENT OF SIGNIFICANCE: This study uncovers a mechanism of copper-induced cell death, termed cuproptosis, in myocardial infarction (MI). It identifies low-density lipoprotein receptor-related protein 6 (LRP6) as a key regulator of copper influx and cuproptosis, revealing a potential target for mitigating copper toxicity in cardiac tissue. Chrysin-7-O-glucuronide (C7Og), a potent LRP6 inhibitor, offers a promising strategy to prevent LRP6-mediated cell death while preserving its protective role in cardiac function. Encapsulating C7Og in a Janus hydrogel enhances its delivery and adhesion, demonstrating significant efficacy in reducing myocardial damage and improving cardiac function in rat and Bama miniature pig models. This work offers new insights into copper homeostasis and presents a potential therapeutic approach for MI treatment.