Functionally modified aptamer conjugates are promising tools for targeted imaging or treatment of various diseases. However, broad applications of aptamer molecules are limited by their in vivo instability. To overcome this challenge, current strategies mostly rely on covalent chemical modification of aptamers, a complicated process that requires case-by-case sequence design, multiple-step synthesis, and purification. Herein, we report a covalent modification-free strategy to enhance the in vivo stability of aptamers. This strategy simply utilizes one-step molecular engineering of aptamers with gold nanoclusters (GNCs) to form GNCs@aptamer self-assemblies. Using Sgc8 as a representative aptamer, the resulting GNCs@Sgc8 assemblies enhance cancer-cell-specific binding and sequential internalization by a receptor-mediated endocytosis pathway. Importantly, the GNCs@aptamer self-assemblies resist nuclease degradation for as long as 48 h, compared to the degradation of aptamer alone at 3 h. In parallel, the tumor-targeted recognition and retention of GNCs@aptamer self-assemblies are dramatically enhanced, indicated by a 9-fold signal increase inside the tumor compared to the aptamer alone. This strategy is to avoid complicated chemical modification of aptamers and can be extended to all aptamers. Our work provides a simple, effective, and universal strategy for enhancing the in vivo stability of any aptamer or its conjugates, thus expanding their imaging and therapeutic applications.

In recent years, nanocarriers based on nucleic acids (NCNAs) have emerged as powerful and novel nanocarriers that are able to meet the demand for cancer cell-specific targeting. Functional dynamics analysis revealed good biocompatibility, low toxicity, and programmable structures, and their advantages include controllable size and modifiability. The development of novel hybrids has focused on the distinct roles of biosensing, drug and gene delivery, vaccine transport, photosensitization, counteracting drug resistance and functioning as carriers and logic gates. This review is divided into three parts: (1) DNA nanocarriers, (2) RNA nanocarriers, and (3) DNA/RNA hybrid nanocarriers and their biological applications. We also provide perspectives on possible future directions for growth in this field.