Aptamers—short, single-stranded DNA or RNA oligonucleotides that fold into target-binding structures—are attractive tools for therapeutics, diagnostics, and biosensing. But one limitation shows up again and again in real-world use: stability. In biological fluids, aptamers can be degraded by nucleases, lose their functional conformation, or get cleared rapidly due to small size. “Enhancing aptamer stability” therefore means engineering aptamers to retain integrity and function under the conditions they must actually operate in—serum, cells, elevated temperatures, long storage, or repeated assay cycles. This article explains the major stability failure modes and the best-established enhancement strategies—organized the way practitioners typically make design decisions. 1) What “Aptamer Stability” Really Means (It’s Not One Thing) When people say “aptamer stability,” they often blend multiple properties: Nuclease stability (biostability): resistance to DNases/RNases in serum, plasma, and tissues. Structural/conformational stability: ability to keep the correct fold that binds the target (especially under ionic changes, crowding, or temperature shifts). Thermal stability: higher melting temperature (Tₘ) and robust folding across a wider temperature range. Circulation stability (pharmacokinetic stability): staying in the bloodstream long enough to matter—often limited by renal filtration for small oligos. Functional stability: maintaining binding affinity/specificity after modifications, storage, repeated use, or immobilization. A…
