A general nanoplatform for nucleotide drug delivery: From molecular binding to antiviral therapy

Nucleoside-based agents represent an important class of therapeutics for viral infections and malignancies. Their pharmacologically active forms, nucleoside triphosphates (TPs), exhibit high polarity and negative charge severely limiting cellular uptake and intracellular utilization. While prodrug strategies used in clinical practice often exhibit limited activation and efficacy, nanocarrier-based TP delivery offers a promising alternative; however, efficient encapsulation of these highly hydrophilic small molecules remains a great challenge. To address this, we developed a rationally designed polymeric carrier PGB, featuring alternating phenylboronic acid and guanidinium groups that bind to conserved nucleotide motifs through multivalent interactions. This design achieves an association constant up to 5.19 × 10⁸ with ATP at pH 7.4, facilitates efficient cytosolic delivery, and enhances antiviral efficacy across multiple viral infection models. In an H1N1-infected mouse model, the nanoparticle formulation demonstrated a markedly improved pharmacokinetic profile compared to the antiviral drug Molnupiravir, effectively suppressed viral replication, reduced pulmonary inflammatory cell infiltration, and preserved lung structure and function. Our study successfully achieved the efficient loading and intracellular delivery of hydrophilic molecules, providing a versatile and broadly applicable platform for nucleotide drug delivery.