Metal-phenolic coordination reconfigures pentacyclic triterpenoid self-assemblies into multifunctional antioxidant nanoparticles for hepatoprotection.

Pentacyclic triterpenoids can form self-assembled structures with diverse morphologies through noncovalent interactions, but their intrinsic hydrophobicity often leads to poor aqueous dispersibility, limited bioavailability, and incomplete realization of their biological activities. Meanwhile, the stable incorporation of polyphenolic actives into hydrophobic self-assembled systems remains challenging because of insufficient component compatibility and mismatched precipitation kinetics. Here, we established a nanoplatform that couples pentacyclic triterpenoid self-assembly with metal-phenolic networks (MPNs). Through dynamic metal-phenolic coordination, polyphenols were enabled to participate in particle construction and property regulation rather than being passively loaded. A comparative analysis of five representative pentacyclic triterpenoids showed that their single-component assemblies formed distinct morphologies, including nanospheres and fibers, whereas Fe2+/dihydromyricetin (DMY) uniformly reconstructed all systems into nanoparticles. This transition, supported by coordination bonding and noncovalent interactions, indicates that MPN formation can redirect the assembly pathway and structural output of pentacyclic triterpenoids. Betulonic acid (BC) was selected as a representative scaffold to construct BC@Fe2+-DMY NPs in situ. The resulting system exhibited good dispersity, favorable surface charge, favorable colloidal stability under the tested conditions, and enhanced radical-scavenging capability. In APAP-induced HepG2 cell injury and mouse liver injury models, BC@Fe2+-DMY NPs showed superior antioxidant, anti-inflammatory, cytoprotective, and hepatoprotective effects compared with free BC and DMY. This work reveals the dual role of MPNs in morphology reconfiguration and functionalization of pentacyclic triterpenoid assemblies, providing a strategy for designing natural product-based nanomaterials with integrated structural and functional attributes.