Phosphorus-containing biomolecules, including nucleotides, cyclic dinucleotides, and related cofactors, play central roles in signaling, immunity, and enzyme regulation. However, the highly anionic nature of canonical phosphate linkages severely limits the therapeutic potential of nucleotide-based modalities by restricting membrane permeability, metabolic stability, and systemic delivery. While charge-neutral or non-canonical phosphorus linkages offer a promising solution, their development remains constrained by synthetic challenges, limited structural diversity, and poor compatibility with oligonucleotide assembly workflows.

Here, we present a unified and modular platform for the direct modification of phosphorus centers within DNA and RNA backbones. Building on recent advances in organophosphorus radical chemistry, this approach enables the selective engagement of diverse reaction partners under mild conditions, overcoming the reactivity and selectivity limitations typically associated with complex nucleotide substrates. The strategy provides access to a broad range of previously inaccessible phosphorus linkages without relying on unstable reagents or extensive protecting group manipulations. 

By decoupling nucleic acid assembly from phosphorus diversification, this platform enables rapid exploration of chemically and functionally diverse backbone architectures. More broadly, it establishes phosphorus as a tunable element for modulating physicochemical and biological properties, opening new opportunities for the development of nucleotide-based probes and therapeutics.