Toward universal binder discovery: Advances in display, computational design and in vivo platforms

Protein binders are fundamental tools in chemical biology, key components of biotechnologies, and the foundation of biologics-based medicines. However, no binder discovery method has achieved the fidelity, speed, and cost-effectiveness required for routine laboratory use. We argue that the field stands at an inflection point. In vitro display platforms are now mature but have continued evolving through macrocyclization methods, covalent chemistries, and massive quantitative datasets-expanding chemical space while deepening mechanistic understanding of selection outcomes. Computational de novo design-which has exploded in power over the past few years-is transitioning from methods requiring specialized expertise to more accessible platforms. Finally, in vivo directed evolution technologies are emerging as a critical frontier, which may deliver the throughput and fidelity needed to finally democratize binder discovery. This review summarizes these advances and points toward a future where binder generation is fast, accessible, and a key driver of the next phase of biological research.