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 MnO2 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.

Immune Exosomes Loading Self-Assembled Nanomicelles Traverse the Blood–Brain Barrier for Chemo-immunotherapy against Glioblastoma

“…Currently, receptor-mediated targeted nanodrug delivery systems often rely on modifying exogenous ligands, such as transferrin aptamers, apolipoprotein E peptides, and iRGD peptides. ,− Notably, these targeted nanodrug delivery systems may combine with endogenous proteins to form protein coronas in vivo , resulting in poor targeting . Therefore, we chose serum EXO with TfR as the coating of NPs, which can fully use endogenous Tf to achieve the capacity to target BBB and glioma cells.…”

Biological Implications and Functional Significance of Transglutaminase Type 2 in Nervous System Tumors

“…KCC009 disrupted fibronectin assembly in the ECM, interfering with its pro-survival characteristics [161]. Recently, in contrast with the findings of Dyer and colleagues, it has been reported that biomimetic nanocomplexes containing TG2 small interfering RNA (siRNA) can sensitize U87MG cells to TMZ increasing apoptosis [162].…”

Image‐guided diagnosis and treatment of glioblastoma

“…116,117 Su et al constructed a core-shell biomimetic nanoprobe (TMPsM) for RNAi therapy of GBM, which was composed of hollow MnO 2 carrying Pep-TPE and siRNA as the core, and TfR-aptamer-modified B16F10 cell membrane as the shell. 118 They proved that TMPsM exhibited the ability of TG2 gene silencing to induce apoptosis in vitro, 119 TG2 stimulated self-assembled AIE imaging to accurately diagnose GBM in vivo, and the released siRNA effectively silenced TG2 expression to induce apoptosis, inhibiting the development of orthotopic U87MG-luciferase tumor. For the first time, TMPsM achieved accurate diagnosis and effective treatment of GBM through TG2-triggered self-assembly imaging and RNAi therapy.…”