Nucleic acid nanotechnology in tumor microenvironment research: from illumination to intervention for enhanced immunotherapy

Nucleic acid nanotechnology has emerged as a transformative tool in tumor research due to several unique properties including exceptional programmability and biocompatibility. The simplicity of their synthesis and chemical modification, their versatility as probes for both nucleic acid and non-nucleic acid targets, and their compatibility with signal amplification strategies make nucleic acid nanostructures ideal for biosensing applications. To date, nucleic acid nanotechnology has been successfully used in the precise detection and monitoring of tumor biomarkers at multiple biological scales. Furthermore, the engineering of sensory and modulable nucleic acid nanostructures has facilitated breakthroughs at the single-cell level in illuminating and reprogramming the tumor microenvironment (TME), thereby advancing tumor diagnostics and therapeutic decision-making. Framework nucleic acids (FNAs) have also shown promise in immunomodulation, offering novel strategies for fine-tuning immune responses in cancer immunotherapy. This review highlights the role of nucleic acid nanotechnology in non-invasive imaging and biomarker profiling of the TME, with a focus on innovative approaches that enhance detection sensitivity and real-time monitoring. Furthermore, the advantages and potential applications of nucleic acid nanotechnology in cancer immunotherapy are discussed. Through a detailed exploration of these advances, this review aims to provide insights into the pivotal role of nucleic acid nanotechnology in deciphering and modulating the TME for enhanced therapeutic outcomes in oncology.