Orally Delivered Antisense Oligodeoxyribonucleotides of TNF‐α via Polysaccharide‐Based Nanocomposites Targeting Intestinal Inflammation

Tumor necrosis factor alpha (TNF‐α) is usually regarded as a potential target for inflammatory bowel disease therapy. Herein, a promising strategy for effective delivery of phosphorothioated antisense oligodeoxyribonucleotide of TNF‐α (PS‐ATNF‐α), targeting the intestinal inflammation based on the interaction of the single chain of triple helical β‐glucan (s‐LNT) with poly‐deoxyadenylic acid [poly(dA)], and the colon‐specific degradation of chitosan‐alginate (CA) hydrogel, is reported. The target gene of PS‐ATNF‐α, with a poly(dA) tail through a disulfide bond (–SS–), interacts with s‐LNT to form a rod‐like nanocomposite of s‐LNT/poly(dA)–SS–PS‐ATNF‐α, which significantly inhibits lipopolysaccharide (LPS)‐induced TNF‐α at the protein level by 38.2% and mRNA level by 48.9% in RAW264.7 macrophages. The nanocomposites carried by the CA hydrogel with the loading amount of 83.5% are then orally administered and specifically released to the inflamed intestine, followed by internalization into intestinal cells such as macrophages, to reduce TNF‐α production by 36.4% and dextran sulfate sodium‐induced inflammation by decreasing myeloperoxidase and malondialdehyde. This study defines a new strategy for the oral delivery of antisense oligonucleotides to attenuate inflammatory response, demonstrating a notable potential for clinical applications in intestine‐inflammation‐targeted therapy.