Thermally driven self-assembly of triterpenoid-fructan supramolecular particles contributes significantly to the efficacy of Zexie Tang against MASH.

The aqueous decoction, the principal method for preparing Traditional Chinese Medicine formulas (TCMF), is presumed to exert therapeutic effects through the synergy of its constituents. However, the fundamental physicochemical transformations occurring during decoction, which may be crucial for efficacy, are poorly understood. In particular, whether and how endogenous polysaccharides participate in forming pharmacologically active supramolecular assemblies is largely unexplored. This study investigated the classic TCMF Zexie Tang and revealed that thermal decoction drives the self-assembly of an inulin-type fructan from Atractylodis Macrocephalae Rhizoma and triterpenoids (alisol A, alisol B, 23-acetyl-alisol B) from Alismatis Rhizoma into stable, functional supramolecular particles, designated as heated microparticles (HMPs, ∼1 μm). These HMPs markedly enhanced the oral bioavailability of the triterpenoids. Consequently, in a murine model of metabolic dysfunction-associated steatohepatitis (MASH), HMPs exerted a potent effect in alleviating liver injury, steatosis, and dyslipidemia. In vitro reassembly experiments and molecular dynamics simulations indicate that hydrophobic and hydrogen-bonding interactions are key drivers of particle formation. This study demonstrates that endogenous polysaccharides actively participate in supramolecular complexes of Zexie Tang, and that heat-induced fructan-triterpenoid assemblies serve as an important pharmacologically active component that substantially contributes to the therapeutic effects, establishing a materials-based link between traditional decoction and efficacy.