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Volume 16
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10.3390/biom16081105
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Review

Design of Spherical Nucleic Acids: From Fast Synthesis to Structural Engineering

by
Yu Fan
1,2,†,
Mei Tsz Jewel Chan
1,† and
Jinyuan Liu
3,*
1
Department of Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong SAR 999077, China
2
Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, Shanghai 201804, China
3
State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomolecules 2026, 16(8), 1105; https://doi.org/10.3390/biom16081105
Submission received: 1 July 2026 / Revised: 25 July 2026 / Accepted: 27 July 2026 / Published: 29 July 2026
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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Abstract

Since the introduction of the spherical nucleic acid (SNA) paradigm in 1996, extensive research has been dedicated to this burgeoning field, yielding groundbreaking advances in biomedicine. Featuring a unique three-dimensional spherical nanoarchitecture composed of highly oriented, densely packed oligonucleotide layers conjugated to a solid or hollow core, SNAs possess extraordinary biological properties, including transfection-reagent-independent cellular internalization and enhanced resistance to nuclease degradation. These synthetic and foundational evolutionary milestones offer profound advantages for the rational design of targeted biomedical therapeutics. In this comprehensive review, recent breakthroughs in the synthetic methodologies and structural designs of SNAs, with a particular emphasis on gold-based templates, are systematically summarized and discussed. Furthermore, the core bottlenecks and future perspectives emerging at the intersection of artificial intelligence and high-throughput screening are highlighted to guide next-generation intelligent nanomedicine development.
Keywords: spherical nucleic acids; aptamer; nanomedicine; gene therapy spherical nucleic acids; aptamer; nanomedicine; gene therapy

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MDPI and ACS Style

Fan, Y.; Chan, M.T.J.; Liu, J. Design of Spherical Nucleic Acids: From Fast Synthesis to Structural Engineering. Biomolecules 2026, 16, 1105. https://doi.org/10.3390/biom16081105

AMA Style

Fan Y, Chan MTJ, Liu J. Design of Spherical Nucleic Acids: From Fast Synthesis to Structural Engineering. Biomolecules. 2026; 16(8):1105. https://doi.org/10.3390/biom16081105

Chicago/Turabian Style

Fan, Yu, Mei Tsz Jewel Chan, and Jinyuan Liu. 2026. "Design of Spherical Nucleic Acids: From Fast Synthesis to Structural Engineering" Biomolecules 16, no. 8: 1105. https://doi.org/10.3390/biom16081105

APA Style

Fan, Y., Chan, M. T. J., & Liu, J. (2026). Design of Spherical Nucleic Acids: From Fast Synthesis to Structural Engineering. Biomolecules, 16(8), 1105. https://doi.org/10.3390/biom16081105

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