Nanoparticles for antiviral nucleotide analogs: approaches and analytical challenges

Nucleoside and nucleotide analogs are an impactful class of antivirals, yet their efficacy is often limited by inefficient intracellular accumulation and enzymatic activation. 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. This review provides a brief context and overview of recent advances in nanoparticle-mediated delivery of phosphorylated antiviral nucleotides, drawing on parallels from oncology, and evaluates the technological advances and limitations influencing their continued development as antiviral carriers.