Homozygous familial hypercholesterolemia (HoFH) presents a persistent and difficult-to-treat condition. This recalcitrance stems largely from loss-of-function mutations within the low-density lipoprotein receptor (LDLR) gene, which severely undermine the efficacy of standard therapeutic regimens. Here, we report a bioinspired "targeting and blockade" strategy for the efficient delivery of functional Ldlr mRNA to hepatocytes. This approach is realized through a rationally designed platform, Szd + AP@ExoE-Ldlr, which integrates APOA1-functionalized exosomes for hepatocyte-targeted delivery with a preemptive macrophage blockade using the clinical ultrasound contrast agent Sonazoid (Szd). The APOA1 modification confers specific recognition by the scavenger receptor class B type 1 on hepatocytes, while the pre-saturation of Kupffer cells with Szd significantly mitigates nonspecific clearance by the mononuclear phagocyte system (MPS). In a HoFH murine model, this synergistic strategy markedly enhanced the accumulation of exosomes in hepatocytes and achieved robust restoration of hepatic LDLR expression. Consequently, it elicited a profound correction of the atherogenic lipid profile and substantially attenuated the progression of atherosclerosis. A comprehensive biosafety evaluation confirmed the excellent biocompatibility of this platform. Our work provides a promising and broadly applicable solution for the treatment of liver-related genetic disorders by simultaneously overcoming the critical barriers of targeted delivery and MPS evasion.