A modular dual-siRNA delivery platform based on GalNAc and click chemistry for multigene targeting

Small interfering RNA (siRNA) therapeutics offer considerable promise due to their gene-specific mechanism of action via Watson–Crick base pairing. While GalNAc–siRNA conjugation has demonstrated success in liver-targeted therapies, addressing complex diseases such as cancer and cardiovascular disorders often requires simultaneous silencing of multiple genes. Here, we report a dual-siRNA delivery platform composed of two modular building blocks: DL05 and B13. DL05 features a GalNAc moiety and an azide group for conjugation, while B13 contains an alkyne group for click chemistry with DL05. Both modules were synthesized efficiently and linked to solid supports for oligonucleotide elongation. A proof-of-concept experiment demonstrated the conjugation of two siRNA strands bearing unnatural nucleotides via click chemistry, followed by annealing with complementary antisense strands to form a dual-target siRNA construct. Structural validation via HPLC and mass spectrometry confirmed the success of this approach, highlighting the potential of this delivery platform for multigene-targeting siRNA therapies. To create your abstract, type over the instructions in the template box below.Fonts or abstract dimensions should not be changed or altered.