Engineering of Nanofibers Embedded with Targeted Nanoparticles Breaks Redox Levers for Glioblastoma Therapy

Abstract Glioblastoma multiforme (GBM), one of the most aggressive brain cancers, presents substantial therapeutic challenges, particularly concerning postsurgical recurrence and inherent drug resistance. In this study, a nanofiber‐based drug delivery system integrating platinum pro‐drugs and hemoglobin into mesoporous silica nanoparticles (HB/HSPt@MS NPs) is reported, which are surface‐modified with poly(ethylene glycol) (PEG) and targeting molecules, and subsequently embedded into nanofibers using an electrostatic spinning approach. Applied to the tumor site, these nanofibers leverage folate receptor overexpression on the tumor and the tumor's redox state to enable precise platinum release, inducing cell death through a targeted drug resistance pathway. The incorporation of hemoglobin is crucial as it disrupts the redox balance within GBM cells by facilitating the influx of iron ions, leading to lipid peroxidation through the Fenton reaction. This induces oxidative stress and overwhelms the cellular antioxidant mechanisms. This dual mechanism of action—direct cytotoxicity through sustained drug release and indirect cytotoxicity through induced oxidative stress—enhances the therapeutic efficacy of platinum drugs. The system effectively bypasses the blood‐brain barrier and reduces systemic toxicity, significantly improving delivery efficacy. Both in vitro and in vivo evaluations demonstrate substantial inhibition of tumor growth and recurrence, highlighting the potential for personalized GBM therapy.