Geniposide-Loaded Mitochondria-Targeted Liposomes for Treatment of Myocardial Ischemia

Geniposide (GP) exhibits therapeutic potential for myocardial ischemia–reperfusion injury (MI/RI) by mitigating apoptosis through mitochondrial function restoration. However, GP’s impact on mitochondrial dynamics, particularly fusion–fission equilibrium, remains unclear, and its clinical application for MI/RI is hindered by nonspecific targeting and potential acute intravascular hemolysis. To address these limitations, we developed mitochondria-targeted nanoliposomes (GP@Lip-TPP) using triphenylphosphonium (TPP), a validated mitochondria-targeting molecule. This nanodelivery system was engineered to precisely transport GP to the mitochondria of ischemic cardiomyocytes for the treatment of MI/RI. Under storage conditions, the nanoformulation exhibited remarkable stability exceeding 20 days and maintained stability during simulated gastrointestinal transit for 42 h. In vitro studies confirmed the nanoparticles’ sustained drug release, good biocompatibility, enhanced cellular uptake, and improved mitochondrial targeting. GP@Lip-TPP significantly reduced apoptosis in hypoxia–reoxygenation (H/R)-injured H9c2 cells, potentially by modulating mitochondrial dynamics toward enhanced fusion and suppressed fission. In a murine MI/RI model, GP@Lip-TPP demonstrated significant cardioprotection, preserving mitochondrial function and reducing apoptosis. This mitochondria-targeted nanotherapeutic approach showcases efficacy in restoring mitochondrial function, underscoring its significant promise as a precision nanomedicine strategy for MI/RI.