Chemically Modified siNA Molecules for Stable RNAi Delivery

The patent applies parameter changes by systematically modifying the chemical structure of siNA molecules through various substitutions including 2′-deoxy-2′-fluoro modifications, 2′-O-alkyl modifications, and phosphorothioate backbone modifications. These parameter changes in molecular structure directly enhance the stability and reliability of siNA molecules while maintaining their RNAi activity, resolving the contradiction between improved reliability and increased complexity.

The patent applies segmentation by dividing the siNA molecule into distinct modular components that can be independently modified. The sense and antisense strands can each receive different chemical modifications (2′-deoxy-2′-fluoro, 2′-O-alkyl, phosphorothioate), allowing systematic expansion of the therapeutic repertoire through combinatorial chemistry while maintaining standardized manufacturing protocols for each modification type, thus balancing adaptability with ease of manufacture.

The patent applies composite materials by creating chimeric siNA molecules that combine different nucleotide types (2′-deoxy-2′-fluoro nucleotides, 2′-O-alkyl nucleotides, phosphorothioate nucleotides) within a single molecule. This composite approach maintains the RNAi effectiveness of the original RNA structure while incorporating chemically modified components that provide enhanced stability and improved compatibility with various delivery systems, thereby resolving the contradiction between effectiveness and stability.