Negative aptamer selection—often called negative selection or counter-selection—is a deliberate filtering step in SELEX(Systematic Evolution of Ligands by EXponential enrichment) designed to remove sequences that bind to the wrong things. Instead of enriching binders to your intended target, negative selection enriches your final pool for what you actually want in real-world use: high specificity, low background, and minimal cross-reactivity. In modern aptamer discovery, negative selection is not “optional polish.” It is one of the most effective ways to prevent selection artifacts—like aptamers that bind to beads, linkers, tags, surfaces, common matrix components, or closely related off-target molecules—from dominating your pool. 1) What “Negative Aptamer Selection” Means (and Why It Exists) During SELEX, you start with a huge randomized DNA/RNA library and iteratively enrich sequences that bind. The catch is that many sequences bind strongly to unintended components in the experimental system: immobilization substrates (e.g., beads, membranes) affinity tags or capture molecules (e.g., streptavidin–biotin systems) blockers, serum proteins, plastic, or assay buffers structurally similar molecules (analogs) that you must not bind Negative selection introduces a decoy binding step: you expose the library to an unwanted target (or “negative target”), then discard the sequences that bind it and keep…
