Enzyme-induced liquid-to-solid phase transition of a mitochondria-targeted AIEgen in cancer theranostics

Enzyme-instructed self-assembly (EISA) is a promising approach to anti-cancer therapeutics due to its precise targeting and unique cell death mechanism. In this study, we introduce a small molecule, DN6, which undergoes nitroreductase (NTR)-responsive liquid-liquid phase separation (LLPS) followed by a liquid-to-solid phase transition (LST) through a gel-like intermediate state, resulting in the formation of nanoaggregates with spatiotemporal control. The reduced form of DN6 (DN6R), owing to its aggregation-induced emission (AIE) and mitochondria-targeting capabilities, has been employed for organelle-specific imaging of tumor hypoxia. The red-emissive DN6R nanoaggregates in situ generated by NTR induce mitochondrial damage and oxidative stress, culminating in apoptosis in cancer cells and spheroids. The organelle-specific targeting, visualization, and therapeutic outcomes achieved by leveraging LST of NTR-responsive AIEgenic DN6 render it as a promising agent for cancer theranostics.