Brain targeted biomimetic siRNA nanoparticles for drug resistance glioblastoma treatment

Glioblastoma multiforme (GBM), the most aggressive intracranial neoplasm, remains incurable at present, primarily due to drug resistance, which significantly contributes to elevated recurrence rates and dismal prognosis. Signal transducer and activator of transcription 3 (STAT3) is a critical gene closely associated with GBM drug resistance and the progression of GBM stem cells (GSCs), making it a promising therapeutic target. In this study, we developed cancer cell membrane-cloaked biomimetic nanoparticles to deliver STAT3 siRNA to reverse drug resistance in homologous GBM. These biomimetic nanoparticles leverage homotypic targeting, rapid endosome escape, and fast siRNA release, leading to efficient in vitro STAT3 knockdown in both temozolomide-resistant U251-TR cells and X01 GSCs. Moreover, benefited from the membrane functionalization, significant prolonged blood circulation, improved blood brain barrier (BBB) penetration and GBM tumor accumulation are achieved by these siRNA biomimetic nanoparticles. Importantly, these nanoparticles effectively inhibit tumor proliferation, significantly extending median survival time in orthotopic U251-TR (43.5 d versus 20 d for PBS control) and X01 GSC-bearing mouse xenografts (52 d versus 19.5 d for PBS control). Altogether, this biomimetic siRNA platform offers a promising strategy for gene therapy targeting drug-resistant GBM.