Nucleic acid-based aptamers have emerged as promising therapeutic entities, particularly in the development of targeted drug delivery systems with remarkable potential for treating a wide spectrum of genetic and acquired diseases. These short nucleic acid sequences, either ribonucleic acids (RNA) or deoxyribonucleic acids (DNA), offer the distinct advantage of precise targeting and the ability to interfere with disease-causing genes or proteins, minimizing off-target effects and enhancing the overall treatment efficacy. Despite their inherent therapeutic potential, their clinical utility has been hampered by various challenges, including rapid degradation, limited cellular uptake, and unintended immune responses. Chemical modification strategies have been extensively explored to overcome these limitations and enhance their pharmacological properties. This chapter provides a comprehensive overview of their chemical modification approaches, supramolecular assemblies, and delivery agents, highlighting their potential in clinical translation.