A Membrane‐Anchoring Self‐Assembling Peptide Allows Bioorthogonal Coupling of Type‐I AIEgens for Pyroptosis‐Induced Cancer Therapy

Abstract Enrichment of photosensitizers (PSs) on cancer cell membranes via bioorthogonal reactions is considered to be a very promising therapeutic modality. However, azide‐modified sugars‐based metabolic labeling processes usually lack targeting and the labeling speed is relatively slow. Moreover, it has been rarely reported that membrane‐anchoring pure type‐I PSs can induce cancer cell pyroptosis. Here, we report an alkaline phosphatase (ALP) and cholecystokinin‐2 receptor (CCK2R) dual‐targeting peptide named DBCO‐pYCCK6, which can selectively and rapidly self‐assemble on cancer cell membrane, and then bioorthogonal enrich type‐I aggregation‐induced emission luminogens (AIEgen) PSs (SAIE‐N 3 ) on the cell membrane. Upon light irradiation, the membrane‐anchoring SAIE‐N 3 could effectively generate type‐I reactive oxygen species (ROS) to induce gasdermin E (GSDME)‐mediated pyroptosis. In vivo experiments demonstrated that the bioorthogonal combination strategy of peptide and AIEgen PSs could significantly inhibit tumor growth, which is accompanied by CD8 + cytotoxic T cell infiltration. This work provides a novel self‐assembly peptide‐mediated bioorthogonal reaction strategy to bridge the supramolecular self‐assembly and AIE field through strain‐promoted azide‐alkyne cycloaddition (SPAAC) and elucidates that pure type‐I membrane‐anchoring PSs can be used for cancer therapy via GSDME‐mediated pyroptosis.