Potential Therapeutic Applications of Spherical Nucleic Acids (SNAs) in Cancer: Key Observations and Insights

Spherical nucleic acids (SNAs) are a unique class of nucleic acid nanotherapeutics characterized by densely packed, radially arranged oligonucleotides surrounding a nanoparticle or molecular core, or core-free nanoscale structures. Compared with conventional linear nucleic acids, SNAs exhibit excellent cellular uptake, resistance to nuclease degradation, and efficient target recognition without the help of transfection agents. This review summarizes SNAs' structural diversity, design principles, and the multiscale delivery barriers they encounter. We mainly focus on liposomal SNAs (LSNAs) as programmable platforms for cancer immunotherapy. We emphasize how lipid chemistry, membrane architecture, and anchor stability control lymphoid distribution, immune-cell uptake, antigen presentation, and strong antitumor immunity, rather than seeing lipids as inert carriers. Furthermore, we also discuss current developments in gene silencing, CRISPR-based genome editing, and stimulus-responsive multimodal therapies, highlighting the significant therapeutic advancements of SNAs like clinical trial NU-0129 and LSNAs like cavrotolimod. Finally, we describe present translational obstacles and potential prospects by using SNAs as next-generation precision immunotherapeutics.