Targeted delivery of PGC-1a gene by gas vesicles-assisted ultrasound cavitation for early treatment of acute kidney injury
Endothelial cell (EC) injury plays a critical part in the occurrence and progression of renal ischemia-reperfusion injury (IRI). PGC-1a, as a master regulator of mitochondrial function, has been identified as a potential therapeutic target for treating injured ECs. Here, fucoidan-plasmid PGC-1a-gas vesicles (Fuc-pPGC-1a-GVs) are synthesized to identify damaged renal ECs at the early stage of renal IRI through the high affinity of fucoidan to P-selectin, and significantly enhance gene transfection efficiency by ultrasound-mediated controlled cavitation, resulting in specific overexpression of PGC-1a in injured renal ECs. In vitro and in vivo evidence reveals that ultrasound-mediated gene transfection with Fuc-pPGC-1a-GVs could ameliorate renal IRI by rescuing the function of ECs, decreasing immune cells infiltration, and alleviating renal tubular injury. Mechanistically, overexpressed PGC-1a in injured renal ECs promotes mitophagy and inhibits ROS production by upregulating BNIP3, BNIP3L and SOD2. This study provides a promising strategy for early and efficient treatment of renal IRI. Overall design: To investigate the potential therapeutic mechanisms of Fuc-pPGC-1a-GVs combined with ultrasound irradiation treatment for renal ischemia-reperfusion injury (IRI), transcriptomic analysis of renal microvascular endothelial cells (RMVECs) was performed comparing the hypoxia/reoxygenation (H/R) group and the H/R+Fuc-pPGC-1a-GVs+US group.