Hyaluronic acid–phosphatidylcholine complexes as reductionist mimics of extracellular vesicle–mediated boundary lubrication in synovial joints

Synovial joints achieve ultra-low friction through the cooperative interaction of multiple molecules. While hyaluronic acid (HA)-associated extracellular vesicles (EVs) are linked to osteoarthritis and boundary lubrication, their exact mechanistic role remains unclear. Here, a reductionist HA–phosphatidylcholine (HA-PC) complexes was introduced to mimic HA–EVs assemblies and unravel their structure-function relationships in joint lubrication. High-molecular-weight HA was mixed with representative gel-phase (hydrogenated soy PC, HSPC) and liquid-phase (1,2-dimyristoyl-sn‑glycero-3-phosphatidylcholine, DMPC; 1-palmitoyl-2-oleoyl-sn‑glycero-3-phosphatidylcholine, POPC) lipids. These results demonstrated that HA binding alters lipid assembly, increases their phase transition temperatures and promotes bilayer spreading upon interfacial contact. Furthermore, lipids disrupt the HA network which enhances its shear-thinning properties. Surface force balance measurements revealed ultralow friction μ∼ 10 –5 –10 –3 that remains robust under high pressure for both HA-HSPC and HA-POPC complex. This study demonstrated the synergy provided by the HA-PC complex and may shed light to the role of synovial fluid HA–EVs as adaptive boundary lubricants, supporting a multicomponent model of synovial lubrication. Statement of Significance Synovial joints including hips and knees maintain ultralow friction – essential for joint health and for suppressing osteoarthritis (OA), a debilitating joint disease affecting millions - through synergistic interactions among multiple molecular constituents, among which extracellular vesicles (EVs) are believed prominent. Growing evidence shows that many EVs are physically associated with hyaluronic acid (HA); however, the mechanical consequences of this coupling, and its disruption in OA, remain unclear. Using a reductionist HA–phosphatidylcholine system that mimics core HA–EV interactions, we unravel their structure–function relationships in joint lubrication. Our results provide insight into how HA–EV assemblies may contribute to efficient pressure-resistant boundary lubrication, and how synovial fluid remodelling of HA in OA may drive lubrication failure and disease progression.