Rational Design of Spherical Nucleic Acids: Expanding Horizons for Precision Nucleic Acid Therapy

Nucleic acid therapy has emerged as a core focus in modern biotherapy owing to its capability of regulating diseases by targeting specific genes. However, key challenges such as nucleic acid susceptibility to enzymatic degradation, low cellular uptake, and poor tissue targeting have severely hindered their clinical translation. Notably, spherical nucleic acids (SNAs), as unique nucleic-acid-based nanoplatforms, offer a compelling solution to these bottlenecks, largely stemming from their geometry-driven advantages. Their high-curvature spherical structure, characterized by a nanoparticle core densely decorated with radially oriented oligonucleotides, endows them with modular flexibility, strong physiological stability, and efficient intracellular accumulation. Given their strong potential in biomedicine, this review systematically summarizes recent advances in the rational design of SNAs and their applications in precision nucleic acid therapy. Moreover, we decipher SNA structure–function relationships in depth to guide rational design, especially highlighting intelligent SNA strategies that respond to diverse disease microenvironments for precise treatment. Additionally, we demonstrate the functional versatility and broad engineering potential of SNAs, underscoring their indispensable role in expanding treatment scenarios. More importantly, this review updates the current knowledge of SNA design and provides actionable guidance for translating more efficient precision nucleic acid therapeutics from basic research to clinical practice.