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 programmable influx- efflux cycles of synthetic nanoassemblies in living cells that expel invasive nanostructures and restore intracellular homeostasis. Specifically, a model photosensitizer-peptide conjugate undergoes multiple redox cycles between methionine (Met) 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, causing perturbations. To counteract these perturbations, 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 of engineering cells to expel intracellular NPs and restore homeostasis paves the way for the generation of innovative interactions between synthetic nanostructures and genetic networks in living cells.