Steering spherical nucleic acids over metabolic organs for improved targeted drug delivery

Spherical nucleic acids (SNAs) represent a class of nanomaterials typically composed of a nanoparticle (NP) core functionalized with a dense shell of oligonucleotides. This architecture confers several advantageous properties, including enhanced cellular uptake, high nuclease stability, low immunogenicity, and minimal cytotoxicity, making SNAs a promising platform for biomedical applications. Nevertheless, several challenges currently hinder their clinical translation, among which unintended accumulation in non-target organs remains a significant limitation. This review begins by introducing the organs involved in the uptake of nanoparticles, providing a concise overview of the characteristics of NP accumulation in major organs such as the liver, kidneys, and spleen. Furthermore, highlights the potential mechanisms underlying these distribution patterns and extends the discussion to SNAs. Subsequently, reviews the latest strategies for improving the in vivo distribution of SNAs from three primary perspectives: modifying the SNA structure, engineering the surface and modulating the microenvironment surrounding SNAs. Finally, based on the current state of SNA research, discusses key challenges facing existing strategies, as well as the promising prospects of this field. It is hoped that this review will provide valuable insights and guidance for the development and rational design of novel SNAs.