Inflammation-responsive framework nucleic acids for ulcerative colitis therapy

Therapeutic oligonucleotides targeting GATA3 have emerged as promising immune-modulating drugs for treating ulcerative colitis (UC). However, achieving effective in vivo delivery of therapeutic oligonucleotides to selectively modulate target cells is challenging due to the intestinal barrier and cellular heterogeneity. Here, we demonstrated the intravenous delivery of GATA3-targeted oligonucleotide (hgd40 DNAzyme) to the intestine utilizing tetrahedral framework nucleic acids (tFNAs). The hgd40 DNAzyme was assembled into tFNAs (hgd40-tFNA) via an inflammation-responsive DNA duplex, thereby enabling its selective release within inflamed cells mediated by cytosolic apurinic/apyrimidinic endonuclease 1 (APE1). We demonstrated that, after intravenous injection, hgd40-tFNA exhibited effective intestinal accumulation and selectively induced potent knockdown of pathogenic gene in inflamed cells while showing low efficiency in normal cells. Notably, when administered to mice with DSS-induced colitis, hgd40-tFNA significantly mitigated weight loss and colonic shortening in the mice by effectively restoring intestinal epithelial homeostasis, showing potent therapeutic efficacy. Our results suggest that the tFNAs can effectively deliver therapeutic oligonucleotides to the intestine and selectively act on intestinal inflamed cells, highlighting their potential for intravenous administration in treating inflammatory intestinal diseases.