Decoction-inspired thermo-mechanical coupling creates hierarchical nanohelix from herbal medicine for lipophagy therapy

Abstract Oral supramolecular nanomedicines often suffer from kinetic trapping, forming metastable aggregates with poor gastrointestinal stability and premature drug release. Conventional assembly methods rarely overcome these barriers. Inspired by the traditional Chinese medicine (TCM) decoction process, which intrinsically combines heating with mechanical stirring, we applied a thermo-mechanical coupling strategy to baicalin and berberine assemblies. Coupled thermal energy and fluid shear drove a transition from kinetically trapped metastable aggregate to thermodynamically stable left-handed nanohelix with an ordered crystalline lattice. This higher degree of structural order conferred improved gastrointestinal tolerance and extended the in vivo mean residence time to 23.06 ± 0.47 h. Sustained systemic exposure activated the AMPK–FoxO1–TFEB–lysosome axis, promoted hepatic lipophagy, and alleviated metabolic dysfunction-associated fatty liver disease in mice. These findings provide a physical chemistry framework for overcoming kinetic traps in supramolecular assembly, elucidate the nanoscale organization underlying traditional decoction, and offer a design strategy for long-acting oral nanotherapeutics.