Glycopolymer P-SF attenuates myocardial ischemia-reperfusion injury by modulating macrophage PANoptosis

Introduction Myocardial ischemia-reperfusion injury (MIRI) remains a critical clinical challenge with limited therapeutic options. Through integrated database analysis and experimental validation, we identified widespread macrophage PANoptosis in the injured myocardium during MIRI. Macrophage-specific NLRC5 knockout mice exhibited attenuated MIRI phenotypes by suppressing PANoptosis, suggesting NLRC5 as a key mediator of this process. However, the upstream regulatory mechanisms remain unclear and therapeutic strategies targeting PANoptosis is worth to explore. Objective This study aimed to elucidate the molecular mechanisms of macrophage PANoptosis in MIRI and develop novel glycopolymer-based nanomaterial targeting this process to improve myocardial recovery. Methods Cell death levels were quantified via fluorescence-based assays, while immunoprecipitation and Western blot were used to validate PANoptosome assembly and pathway activation. Comprehensive database analysis identified a significant correlation between Dectin-1 expression and PANoptosis, which was validated through in vitro and in vivo experimental models. Multiple glycopolymer-based nanomaterials were screened for Dectin-1-mediated PANoptosis regulation. Cardiac targeting efficiency of P-SF was validated using fluorescence and IVIS imaging. Cardiac function and pathology were analyzed via cardiac magnetic resonance (CMR) and histopathology. Results Dectin-1 regulated PANoptosis via the Syk/NOX2/ROS pathway, which orchestrates NLRC5-mediated PANoptosome assembly and subsequent inflammatory cell death. Among screened nanomaterials, P-SF (a P-selectin-targeted glycopolymer capable of self-assembling into micelles in solution) was identified as the most effective inhibitor in suppressing PANoptosis through Dectin-1 binding. IVIS imaging demonstrated preferential accumulation of P-SF in infarcted myocardium, with colocalization to macrophages, correlating with post-injury P-selectin upregulation. P-SF treatment significantly improved cardiac function (mean EF upregulated from 44% to 67%) and reduced myocardial fibrotic area (decreased from 27% to 7%) via downregulation of macrophages PANoptosis. Conclusion Dectin-1-regulated NLRC5-mediated PANoptosis is identified as a novel therapeutic target for MIRI. P-SF, a dual-targeting nanotherapeutic leveraging P-selectin homing and Dectin-1 binding, effectively inhibits macrophage PANoptosis and mitigates myocardial damage, highlighting its translational potential in immune modulation for ischemic heart disease.