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Chemical modification of the phosphodiester backbone is a central strategy to address these challenges. Among these, charge\u2010neutral alkyl phosphonate analogues featuring P\u2500C linkages have attracted considerable attention for their potential to enhance stability and safety. However, general and programmable methods for site\u2010specific 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\u2010mediated C(sp\n                    <jats:sup>3<\/jats:sup>\n                    )\u2500P 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\u2010unrestricted diversification. The resulting alkylphosphonate dimers were transformed into phosphoramidite monomers and incorporated into oligonucleotides by automated solid\u2010phase 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\u2010leukemic efficacy in cellular and primary patient\u2010derived models, underscoring the translational potential of this strategy for next\u2010generation nucleic acid therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/anie.202524814","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T06:59:39Z","timestamp":1766559579000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Photoelectrocatalytic Platform for Sequence\u2010Unrestricted Modification of Oligonucleotide Backbones"],"prefix":"10.1002","volume":"65","author":[{"given":"Kang\u2010Ning","family":"Yuan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Synergistic Chem\u2010Bio Synthesis Frontiers Science Center for Transformative Molecules Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs 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