Engineered Liposomal Quercetin Attenuates Myocardial Ischemia/Reperfusion Injury via Targeted HMGB1-NF-κB Suppression.

Quercetin (QC) is a natural flavonoid with poor bioavailability and unclear precise mechanism in myocardial ischemia/reperfusion (MI/R) injury. We identified high mobility group box-1 protein (HMGB1) as a direct cysteine‑binding target of QC using IAA-yne-based chemical proteomics, which was further validated by cellular thermal shift assay, pull-down experiments, siRNA interference, and bio-layer interferometry experiments. Mechanistic studies revealed that QC binding to HMGB1 inhibits the activation of NF-κB signaling pathway, thereby reduced the release of pro-inflammatory cytokines. To overcome the limitation of QC's delivery, we innovatively engineered myocardial-targeted liposomal nanoparticles (PEG-PEP/QC NPs). Pharmacokinetic analysis revealed this NPs significantly increased the QC's plasma concentration, prolonged the half-life, and, crucially, enhanced the accumulation of QC in cardiac tissue. In the rat MI/R model, this targeted formulation alleviated cardiac dysfunction, suppressed inflammatory response, and reduced myocardial injury. Together, our findings highlight the promise of targeted nanodelivery systems for MI/R therapy.