Chemical signal driven supramolecular network evolution for cancer mitochondrial targeting

Supramolecular hydrogels that respond to disease-associated chemical signals could enable selective therapeutic activity while minimizing effects on healthy tissues. However, achieving adaptive structural reorganization within a simple molecular framework remains challenging. Here we show a chemical signal driven supramolecular hydrogel that undergoes in-situ network evolution in response to H2O2. A hydrogelator forms a homogeneous nanofibrous network that reorganizes into a self-sorted double network containing coexisting thick and thin fibres upon chemical stimulation. This gel-to-gel transition enables spatial patterning and reflects adaptive supramolecular reconfiguration rather than network disassembly. We further show that the hydrogel responds selectively within the elevated oxidative environment of cancer cell mitochondria, inducing localized supramolecular reorganization, mitochondrial disruption and rapid cell death. The hydrogel exhibits pronounced cytotoxicity toward malignant cells such as HeLa cells, while largely preserving non-malignant cells. These findings establish chemical signal driven network evolution as a strategy for translating pathological redox signals into adaptive supramolecular function and selective cancer targeting. Disease-responsive supramolecular hydrogels could enable selective therapy, but adaptive structural reorganization remains challenging. Here, the authors show that a supramolecular hydrogel responds to H₂O₂ by reorganizing into a self-sorted double network, enabling selective cancer cell killing while largely sparing non-malignant cells.