A CD36-targeted aptamer-4-butyl-polyhydroxybenzophenone conjugate with pH-responsive release for liver delivery in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread chronic liver disease worldwide, making efficient targeted delivery systems essential to alleviate its socioeconomic burden. Aptamers are short, single-stranded DNA or RNA oligonucleotides that bind to specific target antigens with high affinity and specificity. Compared with antibody-based therapies, aptamer-based therapies offer the advantages of small size, facile synthesis and low immunogenicity. Herein, we report a novel fatty acid translocase CD36-targeted aptamer-drug conjugate (ApDC), the NAFLD01 aptamer conjugated with 4-(4-(tert-butyl)benzoyl)-2,3-dihydroxyphenyl furan-2-carboxylate (SF), termed ASC, as a targeted delivery platform for MASLD. Results demonstrated that SF significantly reduced body weight, attenuated liver injury and ameliorated lipid accumulation in high-fat diet (HFD)-induced MASLD mice. ASC effectively reduced lipid droplet formation and hepatic injury biomarker levels, while improving antioxidant enzyme levels in MASLD cell models in vitro. A key advantage of ASC is its capacity for targeted SF delivery, which potentially reduces off-target exposure of SF to non-target organs. ASC retained the intrinsic properties of the NAFLD01 aptamer, including high binding affinity and efficient internalization by target cells. Additionally, the acid-labile hydrazone bond in ASC was cleaved in an acidic lysosomal environment. In conclusion, ASC is a promising ApDC delivery platform for MASLD.