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Abstract Oligonucleotide‐based therapeutics represent a transformative modality for treating genetic disorders, yet their clinical translation is often hindered by poor nuclease stability, limited cellular uptake, and sequence‐dependent toxicity. Chemical modification of the phosphodiester backbone is a central strategy to address these challenges. Among these, charge‐neutral alkyl phosphonate analogues featuring P─C linkages have attracted considerable attention for their potential to enhance stability and safety. However, general and programmable methods for site‐specific installation of diverse alkyl groups at the nonbridging oxygen position remain scarce, particularly for sterically demanding secondary and tertiary motifs. Herein, we report a modular photoelectrochemical strategy for direct alkyl modification of oligonucleotide backbones via radical‐mediated C(sp 3 )─P bond formation. This method harnesses the synergistic interplay of photoredox and electrochemical activation to generate alkyl radicals from simple carboxylic acids under mild conditions, thereby bypassing the need for highly reactive Grignard reagents or carbocation intermediates. The protocol accommodates a broad range of alkyl groups and is compatible with all canonical nucleobases, enabling sequence‐unrestricted diversification. The resulting alkylphosphonate dimers were transformed into phosphoramidite monomers and incorporated into oligonucleotides by automated solid‐phase synthesis. Biophysical and biochemical studies showed that these modifications preserve duplex hybridization while enhancing nuclease resistance. Notably, incorporation into the antisense drug Prexigebersen significantly enhanced anti‐leukemic efficacy in cellular and primary patient‐derived models, underscoring the translational potential of this strategy for next‐generation nucleic acid therapeutics.
Yuan et al. (Tue,) studied this question.