Opportunities / ENERGY, DEPARTMENT OF

TIDAL: Target-Induced Droplet Assembly of Ligands

Description (excerpt)

Developed by Los Alamos National Laboratory, TIDAL (Target-Induced Droplet Assembly of Ligands) transforms the small antibody fragments known as nanobodies into a programmable, protein-only material that organizes itself on demand. By harnessing a natural process called liquid-liquid phase separation, TIDAL lets these binders gather into dense, dynamic droplets precisely when they encounter their intended target, giving developers a single platform that can purify proteins without costly resins, deliver drugs as a self-forming slow-release depot and even trap harmful proteins inside living cells. The outcome is a versatile toolkit that lowers production costs, simplifies manufacturing and opens fresh therapeutic and diagnostic possibilities, all from a building block that biology already knows how to make. Overview At the heart of TIDAL is a small, engineered tag, called an encapsulation peptide (EP), that is fused to a nanobody. When many of these tagged nanobodies are present, they undergo liquid-liquid phase separation, similar to what makes oil bead up in water, and they collect into concentrated liquid droplets made entirely of protein. Binding to the target molecule intensifies the effect, so the droplets form most strongly exactly where and when that target is present. Because the assembly is dynamic and reversible, the droplets behave as stimuli-responsive materials whose thickness and flow can be tuned by the target ligand, allowing one design to serve as a purification handle, a delivery vehicle or an intracellular trap. Technology Description TIDAL: Target-Induced Droplet Assembly of Ligands treats the nanobody itself as a structural component rather than merely a binding reagent. Each fusion polypeptide pairs a target-specific nanobody with the encapsulation peptide (EP), and it is the peptide that drives the many weak, cooperative interactions responsible for phase separation. In solution these interactions produce biomolecular condensates, dense droplet phases that concentrate the nanobodies far above their ordinary levels; the presence of the matching ligand pushes the balance further toward condensation. Because condensation is governed by many cooperative contacts rather than a single rigid bond, the droplets stay liquid-like and dynamic, and their formation can be reversed when the trigger is removed. Building on that behavior, the droplets function as programmable modules for delivery, stability or signal enhancement. Their rheology, mea …

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