Dual-functional poly(disulfide) enables "Once-and-for-all" atherosclerosis therapy via precision hepatocyte base...

Area of Science:

• Biotechnology
• Genetic Medicine
• Polymer Chemistry

Background:

• CRISPR base editors show promise for genetic medicine but face delivery challenges.
• Efficient, cell-specific delivery and sustained activity are crucial for clinical translation.

Purpose of the Study:

• To develop a dual-functional polymer for targeted delivery of adenine base editors (ABEs) to hepatocytes.
• To achieve direct cytosolic delivery and durable gene editing for potential atherosclerosis treatment.

Main Methods:

• A poly(disulfide) polymer was engineered with galactose ligands for hepatocyte targeting via asialoglycoprotein receptors (ASGPRs).
• The polymer backbone facilitated direct cytosolic delivery through thiol-disulfide exchange, avoiding endosomal entrapment.
• Adenine base editors (ABEs) were delivered to hepatocytes for gene editing.

Main Results:

• The dual-functional polymer achieved specific hepatocyte targeting and efficient cytosolic delivery of ABEs.
• A single administration resulted in durable editing of the ANGPTL-3 gene.
• In a mouse model, one-dose treatment significantly reduced LDL cholesterol and attenuated atherosclerosis plaque formation.

Conclusions:

• This study presents the first successful single-dose base editing therapy for atherosclerosis prevention and treatment.
• The developed system offers a transformative platform for precision genome medicine in metabolic diseases.
• This approach overcomes key hurdles in CRISPR base editor clinical translation.