“Living Detergents”: An in Situ Detergent Tailoring Strategy for Efficient Membrane Protein Stabilization and Analysis

Abstract Detergents are essential molecular tools for membrane protein (MP) research, yet traditional detergents with static properties often fail to address the diverse and evolving needs of MP studies. To this end, this study introduces “living detergents”, an innovative class of detergents equipped with functional tags that enable bioorthogonal modifications with externally introduced structural elements. This approach allows for not only the parallel generation of new detergents, but also in situ tuning of MP samples within freshly formed detergents. The efficacy of this strategy was demonstrated through the rapid identification of optimal detergents for high‐quality electron microscopy studies of A 2A AR. Overall, this flexible and robust platform enables efficient tailoring of detergents, advancing the exploration of detergent structure‐function relationships in MP research and opening pathways for more specialized solutions for diverse experimental demands.