Protein‐Nanoarchitectures for Low‐Field Intracellular Electro‐Immunomodulation

ABSTRACT Precisely controlling cell function at the cellular level, rather than through macro‐device interfaces, remains a central challenge for advanced electroceuticals. Here, we report a conductive, protein‐mediated nanoarchitecture in which the bifunctional enzyme dehydroquinate dehydratase/shikimate dehydrogenase (DHQ‐SDH) directs the anisotropic assembly of gold nanoparticles (AuNPs) into a chain‐like structure. Stabilized at sub‐saturation stoichiometry, the assembly enables longitudinal plasmonic coupling and establishes an interconnected conductive network, yielding a >3.6‐fold increase in conductivity (2.71 mS/cm). Multi‐scale atomistic modeling (DFT/MD) reveals that this assembly is thermodynamically driven by specific amino acid‐gold interactions associated with electron‐density redistribution. The DHQ‐SDH‐AuNP nanoarchitectures are rapidly phagocytosed, and function as intracellular bio‐nanoelectrodes within RAW 264.7 macrophages. Under a mild external electrical field (100 mV/mm), internalized nanoarchitectures facilitate electrically responsive changes in intracellular redox state and macrophage phenotype, promoting a shift from an M1‐like toward an M2‐like state. This protein‐based bio‐nanoconductor introduces an on‐demand activation strategy for 4D bioelectronic medicine, with potential applications from diabetic wound healing to neural interfaces.