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

Abstract 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.