Glioblastoma (GBM) is the deadliest brain tumor with a high mortality rate [1], [2], [3]. Even though adopting multimodal treatment strategies, median survival has not improved significantly and GBM continues to pose a significant threat to cancer patients [4], [5], [6], [7]. Temozolomide (TMZ) is used as a first-line chemotherapeutic agent to treat GBM [8], [9], [10]. Research has found that tumor cells have high expression of O6-methylguanine-DNA-methyltransferase (MGMT), which is responsible for repairing DNA damage and inducing cell resistance [11]. Due to the existence of DNA repair mechanisms, the ability of TMZ to induce apoptosis in tumor cells may be limited. Therefore, combining chemotherapeutic and non-apoptotic drugs might offer a new way to decrease GBM chemoresistance and enhance the therapeutic efficacy [12].

Ferroptosis as a non-apoptotic cell death, induces tumor cell death and reduces chemoresistance to conventional apoptotic pathways [13], [14], [15], [16]. Luteolin (Lut) is a natural flavonoid compound found in various plants with remarkable anti-tumor and neuroprotective properties [17], [18]. We expect that Lut can not only induce Wnt/β-catenin imbalance and interfere with MGMT, leading to DNA damage-induced apoptosis but also inhibit Nrf2 expression and induce ferroptosis in GBM cells [19], [20], [21]. Therefore, the combination therapy of Lut and TMZ may be used to address chemotherapy resistance issues related to cell apoptosis. According to studies, the main factor affecting the effectiveness of combination therapy is the blood-brain barrier (BBB), which makes it difficult for most drugs to enter the brain [22], [23]. Thus, targeted drug delivery approaches for GBM are urgently needed to overcome systemic side effects and eventually improve patient survival.

Nanotechnology has emerged to improve the efficiency of accurate drug delivery, such as liposomes and polymeric nanocarriers. According to reports, fucoidan (Fuc), a sulfated fucose-rich polysaccharide derived from brown algae, is widely used in targeted drug delivery [24]. Daniel A. Hell et al. have created Fuc nanoparticles that specifically target P-selectin. Such nanoparticles have shown the ability to efficiently carry anticancer agents traverse the BBB and deliver them to tumor tissues [25]. Fuc has multiple biological characteristics, such as resisting inflammation, anti-proliferation, and pro-apoptotic [26]. Therefore, Fuc promotes drug-targeted delivery to tumors and inhibits GBM cell proliferation. Although actively targeted nanocarriers have been constructed, many of them are still mainly distributed in sites such as the liver and kidneys. Consequently, dual, or multi-target strategies are particularly important in brain delivery [27], [28], [29]. Recently, biomimetic nanomaterials with favorable safety profiles have been designed to address these challenges. Exosomes (Exos) are extracellular vesicles with a particle size ranging from 40 to 160 nm, possessing excellent biocompatibility and immune escape ability [30], [31], [32], [33], [34], [35]. More importantly, tumor-derived exosomes can target the tumor cells from which they originate to achieve drug delivery, modifying the EM is more favorable for nanoparticles to achieve drug-targeted delivery to brain tumors [36], [37].

In this work, we attempted to create a biomimetic nano-drug delivery system (EMNPs@TMZ) for targeted therapy against GBM. As shown in Scheme 1, the nanoparticle Fuc-PBA-Lut (FNPs) was self-assembled with TMZ to obtain FNPs@TMZ, and then the biomimetic nanoparticle EM/FNPs@TMZ (EMNPs@TMZ) was constructed using EM camouflage. In the tumor microenvironment (TME), the breakdown of EMNPs@TMZ can be initiated by excessive ROS. The released Lut not only inhibits the Nrf2 expression to induce ferroptosis but also downregulates MGMT through Wnt/β-catenin to promote cell apoptosis. The biodistribution, antitumor efficiency, and biosafety of EMNPs@TMZ were elucidated in an orthotopic GBM mice model. Our results demonstrated that exosome-coated nanoparticles were able to cross the BBB and target tumor sites, significantly enhancing the tumor inhibition effect of chemotherapeutic agents and prolonging the survival time of mice. In brief, a straightforward and highly efficient approach combining ferroptosis with chemotherapy was proposed.