Unnatural Nucleic Acid Aptamers: from SELEX to Tailored Functionalization and Applications

Aptamers have emerged as a versatile and promising class of molecular recognition elements due to their low immunogenicity, negligible batch-to-batch variability, and ease of large-scale synthesis. However, the practical application of natural aptamers is hindered by their susceptibility to nuclease degradation and their sensitivity to environmental factors, such as pH and metal ion concentration, which can significantly affect their binding performance. To address these challenges, the development of unnatural aptamers with enhanced biological stability and expanded chemical functionalities has become an important research focus. This review systematically summarizes the recent advances in the screening of unnatural nucleic acid aptamers, strategies for the structural and functional remodeling of natural aptamers, and the wide-ranging applications of unnatural aptamers. Special attention is given to the underlying mechanisms of aptamer-target interactions and the strategic approaches employed for aptamer optimization. Additionally, the review highlights current challenges and future directions in the field, with the aim of accelerating the discovery and application of unnatural aptamers, diversifying their functional repertoire, and improving their binding performance and environmental adaptability.