Efficient Delivery of Lomitapide Using Hybrid Membrane‐Coated Tetrahedral DNA Nanostructures for Glioblastoma Therapy

Abstract Glioblastoma (GBM) is the most aggressive and prevalent primary malignant tumor of the central nervous system. Traditional chemotherapy has poor therapeutic effects and significant side effects due to drug resistance, the natural blood‐brain barrier (BBB), and nonspecific distribution, leading to a lack of clinically effective therapeutic drugs. Here, 1430 small molecule compounds are screened based on a high‐throughput drug screening platform and a novel anti‐GBM drug, lomitapide (LMP) is obtained. Furthermore, a bionic nanodrug delivery system (RFA NPs) actively targeting GBM is constructed, which mainly consists of tetrahedral DNA nanocages (tFNA NPs) loaded with LMP as the core and a folate‐modified erythrocyte–cancer cell–macrophage hybrid membrane (FRUR) as the shell. FRUR camouflage conferred unique features on tFNA NPs, including excellent biocompatibility, improved pharmacokinetic profile, efficient BBB permeability, and tumor targeting ability. The results show that the LMP RFA NPs exhibited superior and specific anti‐GBM activities, reduced off‐target drug delivery, prolonged lifespan, and has negligible side effects in tumor‐bearing mice. This study combines high‐throughput drug screening with biomimetic nanodrug delivery system technology to provide a theoretical and practical basis for drug development and the optimization of clinical treatment strategies for GBM treatment.