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

Extracellular lipid particles are typically viewed as vesicles, lipoproteins, or cargo carriers. This article proposes the lipid-state exchange (LSE) hypothesis: a framework where cellular lipid states are externalized, remodeled by biological fluids, and sampled by target cells as functional inputs. LSE reframes lipid state as a causal variable linking composition, interfacial organization, and fluid-phase identity to biological function. LSE spans weak, intermediate, and strong forms. Weak LSE aligns with known vesicle and lipoprotein biology. Intermediate LSE emphasizes how carrier form and presentation reshape lipid function. Strong LSE predicts a novel functional layer beyond established particle classes and cargo-driven mechanisms. A key prediction of strong LSE is the existence of non-classical lipid-state exchange particles (non-classical LSEPs). These are lipid-dominant extracellular components with a low abundance of canonical vesicle or apolipoprotein markers. Functionally, they exhibit source-state association and lipid-state-dependent activity, presenting causal effects unexplained by conventional frameworks. Thus, non-classical LSEPs represent a lipid-state-dominant functional entity rather than a marker-defined class. Ultimately, LSE shifts extracellular lipid biology from particle identity and cargo attribution to state causality. It posits that membrane-derived lipid organization acts as a transferable, fluid-edited, and sampleable interface for homeostatic regulation, injury interpretation, and extracellular communication.