Metformin loaded Mn₃O₄@SiO₂ core-shell nanoparticles for glioblastoma multiforme targeted therapy

Glioblastoma multiforme (GBM) presents unique challenges that contribute to a poor early-stage prognosis, primarily due to the difficulty of chemotherapy drugs face in crossing the blood-brain barrier (BBB). Despite decades of research, overall survival rates for GBM patients remain low. However, modified nanoscale biomaterials show promise in enhancing drug delivery and efficacy by effectively penetrating the BBB. In this study, we developed metformin (MET)-loaded Mn₃O₄@SiO₂@cRGD nanoparticles (MSMC NPs) as a targeted pH-responsive drug delivery system for treating glioblastoma (GBM). The nanoparticles demonstrated a high drug-loading capacity of 69.4 ± 3.7 % and an encapsulation efficiency of 11.5 ± 2.1 %. In vitro studies showed that MSMC NPs significantly enhanced cellular uptake in U251 and U87 GBM cells, with a 2.5-fold increase in fluorescence intensity compared to non-targeted nanoparticles. The pH-responsive release of MET reached 70 % at pH 5.5, compared to only 30 % at pH 7.4 over 48 hours. MSMC NPs resulted in a 55.6 % reduction in U251 cell viability and a 43.4 % decrease in U87 cell viability at a 15 mM MET concentration, significantly outperforming free MET. Furthermore, the nanoparticles inhibited cell migration by 80 % in a 3D spheroid model and increased apoptosis rates by 40 % in U251 cells and 35 % in U87 cells. These findings highlight the potential of MSMC NPs as a targeted, pH-responsive, and theranostic platform for improving GBM treatment by enhancing drug delivery and minimizing off-target effects. This study establishes a foundation for developing Mn₃O₄-based nanomedicines for precise cancer therapy.