Targeted PGC-1α gene delivery by GV-assisted ultrasound cavitation for renal ischemia-reperfusion injury therapy

Endothelial cell (EC) injury plays a critical part in the occurrence and progression of renal ischemia-reperfusion injury (IRI). PGC-1α, as a master regulator of mitochondrial function, has been identified as a potential therapeutic target for treating injured ECs. Here, fucoidan-plasmid PGC-1α-gas vesicles (Fuc-pPGC-1α-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 the specific overexpression of PGC-1α in injured renal ECs. <i>In vitro</i> and <i>in vivo</i> evidence reveal that ultrasound-mediated gene transfection with Fuc-pPGC-1α-GVs could ameliorate renal IRI by rescuing the function of ECs, decreasing immune cell infiltration, and alleviating renal tubular injury. Mechanistically, overexpressed PGC-1α in injured renal ECs promotes mitophagy and inhibits ROS production by upregulating BNIP3, BNIP3L, and SOD2. This study provides a promising strategy for the early and efficient treatment of renal IRI.