TfR Aptamer Enhanced Blood‐Brain Barrier Penetration of Biomimetic Nanocomplexes for Intracellular Transglutaminase 2 Imaging and Silencing in Glioma

Abstract Engineering a versatile nanocomplex integrating effective penetration of the blood‐brain barrier (BBB), accurate diagnosis, and boosting therapy has always been an intractable challenge in glioblastoma multiforme (GBM). Herein, biomimetic nanocomplexes (TMPsM) for single intracellular transglutaminase 2 (TG2)‐triggered self‐assembly imaging and RNAi therapy for GBM are subtly developed. To prove the concept, transferrin receptor (TfR) aptamer‐modified brain metastatic tumor cell membrane is prepared as the shell for dual BBB targeting capability and prolonged blood retention time. Upon targeting entering into GBM, hollow MnO 2 is decomposed to release KKGKGQQ‐tetraphenylethene (Pep‐TPE) and siRNA. Owing to TG2 dependence, the non‐emissive Pep‐TPE would be self‐aggregated to induce the emission turn‐on in GBM that contain overexpressed TG2. The resulting aggregation‐induced emission fluorescence imaging with a high signal‐to‐noise ratio can achieve the precise localization of the tumor and dynamic detection of TG2 activity, thereby allowing the GBM accurate diagnosis. Notably, the TG2 can be silenced by the released siRNA to cause cell apoptosis and increase chemotherapeutic sensitivity, ultimately realizing excellent antitumor efficacy. In vitro and in vivo results demonstrate that the as‐prepared TMPsM indeed possess superior BBB penetration, precise diagnosis, and effective therapy of GBM. The proposed strategy may pioneer a new path for the theranostics of brain tumors.