Restoring intracellular homeostasis disrupted by synthetic nanoassemblies.

Cells have evolved to defend against perturbations by maintaining their intrinsic homeostasis to survive. However, no intrinsic pathway exists for them to expel new-to-biology synthetic nanostructures. Here we establish crosstalk between supramolecular transformations and genetic responses, achieving programmable influx-efflux cycles of nanoassemblies in living bacterial cells to restore redox and energy homeostasis. Specifically, a model photosensitizer-peptide conjugate undergoes multiple redox cycles between methionine and methionine sulfoxide (MetO), resulting in reversible morphological transformations between nanofibers (NFs) and nanoparticles (NPs). Upon irradiation, the oxidized peptide NPs are internalized into bacteria. To counteract the perturbations caused by internalized NPs, engineered bacteria activate the expression of MetO reductases in response to photo-oxidative stress. The internalized NPs are intracellularly enzymatically reduced such that they are expelled as reduced NFs, setting the stage for subsequent cycles. The concept presented here paves the way for the interlinked network between dynamic supramolecular assemblies and cellular regulatory behaviors.