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Many analogs are administered as nucleoside prodrugs, dependent on host or viral kinases for sequential phosphorylation, with the first monophosphate-forming step widely considered rate-limiting. Medicinal chemistry strategies such as utilizing masked-phosphate prodrugs may improve uptake and activation, but require alternative metabolic processing to generate the active triphosphate. Nanoparticle delivery provides an alternative or complementary approach by directly encapsulating phosphorylated nucleotide analogs. Nanoparticles made from materials including lipids, polymers, dendrimers, or polysaccharides can protect phosphorylated drugs from degradation, improve cellular uptake, and enable controlled or tissue-specific release. 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