Manuscript number: 202012578 Title: A Supramolecular Bait to Trigger Non-equilibrium Co-assembly and Clearance of Aβ42.

In the living systems, the non-equilibrium states that control the assembly-disassembly of cellular components underlie the gradual complexification of life, whereas in the nonliving systems, most molecules follow the laws of thermodynamic equilibrium to sustain dynamic consistency. However, very little is known about the roles of non-equilibrium states of interactions between supramolecules in living systems. Here, we identified a non-equilibrium state of interaction between supramolecular lipopolysaccharide (LPS) and Aβ42, an aggregate-prone protein that causes Alzheimer's disease (AD). Structurally, the polymerized propagation of Aβ42 presents a specific groove that is recognized by the amphiphilicity of LPS bait in a non-equilibrium manner. Functionally, the transient complex elicits a cellular response to clear extracellular Aβ42 deposits via an endolysosomal mechanism in neuronal cells. Since the impaired clearance of toxic Aβ42 deposits correlates with AD pathology, the non-equilibrium interaction between LPS and Aβ42 could represent a useful target for the development of AD therapeutics.