The Lipid-State Exchange Hypothesis: A Falsifiable Framework for Lipid-State Causality in Extracellular Lipid-Containing Particles

Extracellular lipid-containing particles are usually interpreted as extracellular vesicles, lipoproteins, soluble lipid mediators, or carriers of molecular cargo. This article proposes the lipid-state exchange hypothesis (LSE), a falsifiable framework in which cellular or tissue lipid states can be externalized, partially retained, remodeled by biological fluids, and sampled by target cells or clearance systems as functional state inputs. LSE reframes lipid state as a causal variable in extracellular particle biology, linking lipid composition, interfacial organization, carrier presentation, and fluid-phase identity to biological function.LSE is developed in weak, intermediate, and strong forms. Weak LSE places lipid-state function within known extracellular vesicle and lipoprotein biology. Intermediate LSE emphasizes that carrier form, interfacial presentation, and fluid-phase identity can reshape lipid function. Strong LSE predicts a lipid-state-dependent functional layer beyond established extracellular particle classes and cargo-centered mechanisms.The key empirical prediction of strong LSE is the existence of non-classical lipid-state exchange particles (non-classical LSEPs). Operationally, these candidates are expected to appear as extracellular lipid-dominant particle-like or complex-like components with low canonical extracellular-vesicle and classical apolipoprotein markers. Functionally, they are defined by source-state association, lipid-state-dependent activity, and positive causal residuality when conventional particle-, cargo-, and artifact-based frameworks cannot sufficiently explain their effects. Thus, non-classical LSEPs are not proposed as a marker-defined particle class, but as a lipid-state-dominant functional entity.At a broader level, LSE shifts extracellular lipid biology from particle identity and cargo attribution to state causality. It opens a conceptual space in which membrane-derived lipid organization itself may act as a transferable, fluid-edited, and biologically sampleable state-bearing interface for homeostatic regulation, injury interpretation, and disease-relevant extracellular communication.