Provided is a modified double-stranded oligonucleotide, in which the sense strand comprises a nucleotide sequence 1, the anti-sense strand comprises a nucleotide sequence 2, the nucleotide sequences 1 and 2 are both 19 nucleotides in length, and in the direction from 5′ end to 3′ end, nucleotides at positions 7, 8 and 9 of the nucleotide sequence 1 and nucleotides at positions 2, 6, 14 and 16 of the nucleotide sequence 2 are all fluoro-modified nucleotides, and each nucleotide at other positions is independently one of non-fluoro-modified nucleotides. Further provided are a pharmaceutical composition and a conjugate comprising the oligonucleotide, and pharmaceutical use thereof.

Provided are a small interfering RNA (siRNA) molecule which inhibits the expression of the PCSK9 gene and a pharmaceutical composition thereof, as well as a method for reducing the expression level of the PCSK9 gene by using the siRNA molecule or the pharmaceutical composition thereof. The siRNA molecules may be used to treat and/or prevent PCSK9 gene-mediated diseases.

A major hurdle in the treatment of cancer is chemoresistance induced under hypoxia that is characteristic of tumor microenvironment. Triptolide, a potent inhibitor of eukaryotic transcription, possesses potent antitumor activity. However, its clinical potential has been limited by toxicity and water solubility. To address those limitations of triptolide, the present disclosure designed and synthesized glucose-triptolide conjugates (glutriptolides) and demonstrated their antitumor activity in vitro and in vivo. The glutriptolides disclosed herein possess improved stability in human serum, greater selectivity towards cancer over normal cells and increased potency against cancer cells. Importantly, the glutriptolides are more potent against cancer cells under hypoxic conditions in contrast to existing cytotoxic drugs. These glutriptolides also exhibit sustained antitumor activity, prolonging survival in a prostate cancer metastasis animal model. Together, these findings suggest a new strategy to overcome chemoresistance through conjugation of cytotoxic agents to glucose.

Disclosed herein are engineered oligonucleotides for selective inhibition of polypeptide expression and activity. Also disclosed herein are methods of selectively inhibiting polypeptide expression and activity contacting an engineered oligonucleotide with a polynucleotide encoding the polypeptide.

The disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting an alpha-2A adrenergic receptor (ADRA2A) gene, as well as methods of inhibiting expression of an ADRA2A gene and methods of treating subjects having an ADRA2A-associated disease or disorder, e.g., a primary tauopathy or Alzheimer's disease, using such dsRNAi agents and compositions.

Provided is a series of homologous small molecule immune agonists and novel bifunctional immune targeting compounds having targeting and immune activation functions, which are obtained by coupling the small molecule immune agonists to targeting drugs. The resulting immune targeting compounds are beneficial for enhancing immune activation effects, and anti-tumor and other disease fighting effects of the targeting drug. The enhanced effect is produced from a synergy of immunological anti-tumor factors (such as IFN-γ) and inhibition at pathogenic targeting sites.

Provided herein are methods, compounds, and compositions useful for targeted delivery of compounds to non-native cells ectopically expressing cell surface receptors. Such methods, compounds, and compositions are useful, for example, in gene therapy mediated ectopic expression of cell surface receptors and targeted delivery of compounds, such as conjugated oligonucleotides, to the non-native cells ectopically expressing cell surface receptors. Such methods, compounds, and compositions can be useful, for example, to treat, prevent, delay or ameliorate disease in an individual by targeted reduction of a gene of interest in the non-native cell ectopically expressing cell surface receptors.

Disclosed are novel D-dimer specific aptamers and methods of their use.

Nanoparticles include a polymeric core and a high density lipoprotein (HDL) component where the ratio by weight of the HDL component to the polymeric core is in a range from about 1:9 to about 9:1, such as about 75:25 or less or about 7:3 or less. The nanoparticles may also include a mitochondria targeting moiety. The nanoparticles may be used to treat or prevent atherosclerosis or to maintain lipid homeostasis.

The present disclosure provides methods of reducing the level of acetylated Tau in a neuron or a glial cell in an individual, the methods involving administering to the individual a prodrug that is converted in the individual to salicylate. The present disclosure provides methods of treating a tauopathy in an individual, the methods involving administering to the individual a prodrug that is converted in the individual to salicylate.