Glycopolymeric nanoparticles transported by activated platelets protect ischemic myocardium by alleviating PANoptosis through targeting macrophage Dectin‐1

Myocardial ischemia–reperfusion (IR) injury poses a great threat to human health. In recent years, targeted modulation of immune and thrombotic responses has emerged as a promising therapeutic strategy. Here, we develop a glycopolymeric nanoparticle with fucose and sialic acid segments ( NP‐SF ), with enhanced affinity to Dectin‐1, a critical immunoregulatory target, thus suppressing inflammatory responses of macrophages. Additionally, as the mimic of P‐selectin glycoprotein ligand‐1 (PSGL‐1), NP‐SF leverages activated platelets for targeted delivery to ischemic myocardium and suppresses platelet aggregate formation. In murine IR models, NP‐SF significantly reduces inflammation and infarcted size, subsequently improving cardiac function. NP‐SF is enriched in injured myocardium, where it is retained by macrophages and attenuates pro‐inflammatory macrophage infiltration. Mechanistically, NP‐SF downregulates spleen tyrosine kinase (SYK) signaling, markedly inhibiting PANoptosis by suppressing NLR family CARD domain containing 5 (NLRC5) and PANoptosome complex formation. This cascade attenuates pro‐inflammatory cytokine release. In conclusion, NP‐SF leverages platelet hitchhiking and Dectin‐1 interactions as a dual‐targeted therapeutic agent to resolve macrophage‐driven PANoptosis, offering a translatable strategy for IR injury.