A metabolic amplification strategy for spherical nucleic acid immunogenicity driven by simvastatin-CpG codelivery

Spherical nucleic acids (SNAs) are a promising platform for immunotherapy, although their limited innate immune activation may constrain therapeutic performance. Here, we report a simvastatin-CpG SNAs (S-SNAs) system that integrates a metabolic modulator with CpG to enhance immune activation. Mechanistically, simvastatin is found to potentiate CpG-induced innate immune signaling, likely through modulation of the mevalonate pathway, resulting in regulated macrophage activation in vitro. Integration into the SNAs architecture is associated with improved cellular uptake and enhanced RBD-specific humoral immune responses in vivo. In a murine melanoma model, the engineered S-SNAs exhibit antitumor activity and are associated with prolonged survival under the experimental conditions, without evident systemic toxicity. Overall, this work suggests that metabolic modulation may represent a useful strategy for improving the immunological performance of nucleic acid-based nanostructures.