GDF15 nanotherapy ameliorates NLRP3-associated redox imbalance and cardiac injury in sepsis

Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication of sepsis, characterized by acute cardiac dysfunction and high mortality. Despite its prevalence and severity, SICM lacks effective targeted therapies. Therefore, we developed macrophage membrane-coated PLGA nanoparticles (MGP) for the targeted delivery of recombinant human GDF15 (rhGDF15), aiming to enhance its therapeutic efficacy. In this study, MGP was designed to encapsulate rhGDF15. MGP displayed favorable stability and biocompatibility in vitro and significantly improved left ventricular function and contractility in a lipopolysaccharide (LPS)–induced murine SICM model. Mechanistically, GDF15 binds to MYPT1, inhibiting AKT-mediated phosphorylation of YBX-1 at serine 102 and preventing its nuclear translocation. Cytosolic retention of YBX-1 suppressed NLRP3 inflammasome activation and IL-1β release, which are critical drivers of inflammation and oxidative stress in SICM. This redox-inflammatory link was supported by DHE staining, which demonstrated that MGP treatment attenuated LPS-induced superoxide production. Furthermore, dual-luciferase reporter assay and Ybx-1 knockout experiments confirmed that YBX-1 regulates Nlrp3 expression. Collectively, the study has established a biomimetic nanocarrier that enhances rhGDF15 delivery and delineated a novel GDF15-MYPT1-YBX-1 axis that regulates NLRP3-driven inflammation and oxidative stress in SICM, providing a mechanistic basis for therapeutic intervention in septic cardiac injury. • Macrophage membrane-coated nanoparticles (MGP) enable cardiac-targeted rhGDF15 delivery, enhancing therapeutic efficacy. • GDF15 binding to MYPT1 inhibits YBX-1 phosphorylation, thus blocking NLRP3 inflammasome activation and IL-1β release. • MGP attenuates superoxide overproduction, mitigating myocardial oxidative injury linked to NLRP3-driven inflammation.