OH-optimized rational design of binary phytochemical hydrogels to combat multidrug-resistant fungal infections via CWI-MAPK pathway modulation.

The unique design of low molecular weight hydrogels (LMWH) without carriers has sparked great interest in biomedical applications, yet the construction of binary LMWH remains elusive due to the lack of a theoretical framework linking structure and assembly. Hence, we proposed an innovative theoretical framework, in which a subtle -OH change in parent structures triggers the interconversion of nanoparticles and nanofibers. This framework hinges on a pair of hydrophobic planar small molecules with only one -OH difference, self-assembling into binary LMWH at 1:1 ratio. Notably, LMWH featuring coptisine and chrysin exhibits superior antifungal efficacy against multidrug-resistant Candida auris compared to the clinical first-line drug fluconazole. By electrostatic adsorption, Candida auris with negative charges can specifically adhere to LMWH with positive charges, facilitating the further exertion of LMWH's pharmacological effects. This leads to the activation of the CWI-MAPK pathway, disrupting the polysaccharide components in the fungal cell wall, inhibiting cell wall biosynthesis, and exerting an antifungal effect. Subsequently, this process reduces inflammation and promotes wound healing. This carrier-free, environmentally friendly strategy has significantly enhanced our understanding of the intricate relationship between structure and assembly, and has paved the way for the theory-guided construction of binary LMWH functional biomaterials with antifungal properties.