Engineered Multifunctional Hydrogel Delivering Novel CBX7 Inhibitor Modulates Cuproptosis Via Liquid–Liquid Phase Separation to Restore Cardiac Function in Aged Myocardial Infarction

This study starts from the senescence-associated impairment of cardiac repair, and focuses on the functional difference of CBX7 between young and aged hearts. It reveals that CBX7 interacts with ATP7A via liquid–liquid phase separation, which disturbs copper homeostasis and triggers cuproptosis. A selective inhibitor δ-Amyrenone is obtained through high-throughput screening. A multifunctional hydrogel is further constructed for targeted delivery and controlled release. Combined with single-cell RNA sequencing, the cuproptosis-related cell subpopulations are identified. The therapeutic efficacy is systematically validated in aged mouse and porcine models, offering a new strategy for the intervention of age-related myocardial injury.

 This work suggests that protein phase separation may serve as an important regulatory mechanism in senescence and metabolism-related diseases, with potentially broad implications in maintaining metal ion homeostasis. The combination of hydrogel-mediated controlled drug release and microenvironment regulation provides a multimodal therapeutic strategy for tissue repair. Future research can further explore the dynamic functions of CBX7 in tissues across different age groups, as well as the roles of cuproptosis in other age-related diseases, opening new avenues for developing interventions targeting senescence-associated pathological processes.

Source: Advanced Science

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