Authors
Zhelong Li, Bo Zhang, Chunmao Liu, Wei Wang, Guoping Li, Bingzhang Xu, Feng Liu, Xinyu Li, Chuan Dong, Ping Zhao, Changyang Xing, Lijun Yuan
Published in
Biomaterials. Volume 335. Pages 124399. Jun 22, 2026. Epub Jun 22, 2026.
Abstract
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.
PMID:
42341362
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.
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