Supramolecular hydrogels coassembled from drugs and natural low-molecular-weight gelators (LMWGs) offer favorable physicochemical properties, tunable mechanics, and controlled drug release; however, elucidating their in situ fibrillar architecture remains a major challenge. Here, we report a fully natural G-quadruplex hydrogel formed by coassembling 5'-guanosine monophosphate (GMP) with phytic acid (PA), which serves as both a natural cross-linker and a bioactive therapeutic molecule. Systematic modulation of the GMP/PA ratio revealed a delicate compositional balance governing gel formation, mechanical strength, and pH-dependent molecular interactions. Small- and wide-angle X-ray scattering (SWAXS) combined with CRYSOL-assisted atomistic modeling resolved the hierarchical organization of GMP fibrils and demonstrated that PA promotes surface clustering and interfibril bundling through multivalent electrostatic interactions. Molecular dynamics simulations further confirmed PA-mediated stabilization of the G-quadruplex assemblies under hydrated conditions. Kinetic analysis revealed that densification of fibrillar networks effectively slowed scaffold degradation and enabled sustained PA release, transitioning from zero- to first-order kinetics with increasing structural order. Collectively, this study establishes a direct correlation between molecular architecture, mechanical strength, and release dynamics, presenting a structural framework for the rational design of bioactive, G-quadruplex-based hydrogels for advanced drug delivery applications.
Yen et al. (Tue,) studied this question.