Molecularly Programmed Spherical Nucleic Acids for Precision Nanomedicine

Precision therapy is transforming clinical oncology and disease management by moving beyond one-size-fits-all regimens. However, its full realization remains limited by challenges in therapeutic design and intracellular delivery─particularly the need for cell-type-biased uptake, molecular specificity, and spatiotemporal control of bioactive agents in vivo . Spherical nucleic acids (SNAs), programmable nanostructures consisting of a nanoscale core densely functionalized with radially oriented oligonucleotides, offer a powerful platform to address these barriers. Their three-dimensional architecture enables efficient cellular internalization through scavenger receptor-mediated endocytosis or ligand conjugation. Meanwhile, the densely packed oligonucleotide shell enhances local ligand avidity, provides steric protection against nuclease degradation, and serves as a versatile scaffold for loading diverse therapeutic cargos. Beyond structural advantages, the intrinsic sequence programmability of the DNA shell─enabling sequence-specific molecular recognition and stimulus-responsive conformational switching─confers exceptional operational versatility. This molecular programmability allows SNAs to integrate endogenous or exogenous cues for context-dependent activation, triggered cargo release, and hierarchical, logic-gated multistep therapeutic actions tailored to pathological microenvironments. In this review, we summarize key design principles governing the structural and molecular programming of SNAs, survey in vivo engineering strategies for precise delivery and activation, and highlight recent applications across gene modulation, chemotherapy, photodynamic and photothermal therapy, immunotherapy, and combination therapies. By integrating these advances, we propose a conceptual framework for the development of next-generation SNA-based nanomedicines that couple molecular programming with clinically relevant precision in space, time, and therapeutic modality.