Photo‐Controlled MUC1 Ablation via Steric Locking of Turn‐On Reactors Enhances Pyroptosis‐Immunotherapy of Triple Negative Breast Cancer

Mucin 1 (MUC1) is aberrantly upregulated in triple-negative breast cancer (TNBC) cells and presents major roles in orchestrating TNBC pathogenesis and therapeutic resistance. Herein, a bioorthogonal MUC1-binding strategy is reported to install MUC1-lockable aggregation-induced emission theranostic reactor (AIETR) onto MUC1 for pyroptosis-immunotherapy while enabling in situ MUC1 visualization. TNBC-bearing hosts are first treated with 1,3,4-O-acetyl-N-azidoacetylmannosamine-containing bioresponsive nanoassemblies to generate azido groups on MUC1 via sialic acid metabolism pathway. Dibenzocyclooctyne and MUC1-binding aptamer arms in AIETR can separately bind with azide moieties and aptamer binding domains in MUC1 of glycoengineered TNBC cells and restrict intramolecular rotation to activate their AIE-dependent reactive oxygen species (ROS) generation and fluorescence imaging capacity. The proximity-dependent ROS damage abolishes membrane MUC1 to activate pyroptosis cascades. Moreover, treatment-enabled MUC1 inactivation also ameliorates MUC1-dependent immunosuppression in TNBC microenvironment to boost anti-TNBC immunity. This study offers an effective approach for precision TNBC theranostics in the clinic.