Reprogramming ligand-receptor interactions via a self-powered molecular engine for proton-responsive regulation of cellular motility.

Manipulation of ligand-receptor interactions (LRIs) in a user-defined manner is one of the effective ways to regulate cell motility and disease progression. Molecular engines orchestrate LRIs to regulate cell motility by harnessing various forms of energy within physiological surroundings. However, engineering chemical engines remains largely unexplored, primarily due to the insufficient chemical cue density, uncertain conformational changes of scaffolds, and a limited repertoire of environment-responsive switchable scaffolds. Enzymatic biofuel cells (EBFCs) are electrochemical devices that convert biofuels into other accessible energy through electrochemical reaction for the construction of self-powered molecular tools, offering a viable strategy to overcome the above limitations. Here, we present an enzyme biofuel cell-based self-powered molecular engine (EBFC-SME) for rewiring chemical cues-based LRIs and regulating cell motility. We employ EBFC-SME as a proof-of-concept platform for reprogramming proton-responsive HGF/c-Met interaction. The system comprises a glucose dehydrogenase (GDH)-incorporated bioanode and a bilirubin oxidase (BOD)/functional nucleic acids (FNAs)-encapsulated iron-alginate (IA) hydrogel-coated biocathode. Through glucose-initiated redox reactions, this configuration enables the EBFC-SME to generate abundant protons and release FNAs. These products subsequently mediate the in-situ assembly on tumor cell membrane, which blocks c-Met pathway activation and ultimately suppresses tumor cell migration. Different from conventional chemical engines, the EBFC-SME efficiently regenerates chemical cues via intrinsic energy conversion reactions for the manipulation of scaffold-mediated LRIs. This EBFC-SME platform provides a robust "sensing-conversion-initiation" tool for the chemical regulation of cellular motility, holding significant promise in precision biomedicine.