Gene therapy is a revolutionary treatment approach in the 21st century, offering significant potential for disease prevention and treatment. However, the efficacy of gene delivery is often compromised by the inherent challenges of gene properties and vector-related defects. It is crucial to explore ways to enhance the curative effect of gene drugs and achieve safer, more widespread, and more efficient utilization, which represents a significant challenge in amplification gene therapy advancements. Spherical nucleic acids (SNAs), with their unique physicochemical properties, are considered an innovative solution for scalable gene therapy. This review aims to comprehensively explore the amplifying contributions of SNAs in gene therapy and emphasize the contribution of SNAs to the amplification effect of gene therapy from the aspects of structure, application, and recent clinical translation - an aspect that has been rarely reported or explored thus far. We begin by elucidating the fundamental characteristics and scaling-up properties of SNAs that distinguish them from traditional linear nucleic acids, followed by an analysis of combined therapy treatment strategies, theranostics, and clinical translation amplified by SNAs. We conclude by discussing the challenges of SNAs and provide a prospect on the amplification characteristics. This review seeks to update the current understanding of the use of SNAs in gene therapy amplification and promote further research into their clinical translation and amplification of gene therapy.