Brain-targeting metastatic tumor cell membrane cloaked biomimetic nanomedicines mediate potent chemodynamic and RNAi combinational therapy of glioblastoma

The complex genetic heterogeneity of glioblastoma (GBM) together with the existence of blood brain barrier (BBB) renders GBM essentially incurable. In this paper, a brain-targeting metastatic tumor cell membrane cloaked biomimetic nanomedicine that potently induces cascade chemodynamic and RNA interference (RNAi) is developed for combinational GBM therapy. The designed nanomedicines are constructed from metastatic melanoma cell membrane, charge-conversional middle layer, and siRNA complexed polyethyleneimine xanthate (PEX). PEX chelates the abundant copper ions in tumor cells and then reacts with intracellular glutathione (GSH), resulting in GSH depletion and the reduction of Cu²⁺ to Cu⁺, followed by reacting with H₂O₂ and producing •OH via Fenton-like reaction. Interestingly, the acidic conditions in endo/lysosomes accelerate siRNA release, inducing potent gene silencing of the anti-apoptotic B-cell lymphoma 2 (Bcl-2), lead to multiple molecular cascades that readily induces GBM cell apoptosis. The results also demonstrate that this nanomedicine exhibits efficient BBB penetration via decreasing the tightness and interacting with the adhesion molecules in endothelial cells. More importantly, improved therapeutic efficacy with extended survival rates are achieved in both local melanoma and orthotopic GBM tumor models, suggesting that the chemodynamic and gene combinatorial therapy mediated by the biomimetic nanomedicines shows promising potential in treating GBM and brain metastases.