Brain‐Targeted HFn‐Cu‐REGO Nanoplatform for Site‐Specific Delivery and Manipulation of Autophagy and Cuproptosis in Glioblastoma

Abstract

Durable glioblastoma multiforme (GBM) management requires long‐term chemotherapy after surgery to eliminate remaining cancerous tissues. Among chemotherapeutics, temozolomide is considered as the first‐line drug for GBM therapy, but the treatment outcome is not satisfactory. Notably, regorafenib, an oral multi‐kinase inhibitor, has been reported to exert a markedly superior effect on GBM suppression compared with temozolomide. However, poor site‐specific delivery and bioavailability significantly restrict the efficient permeability of regorafenib to brain lesions and compromise its treatment efficacy. Therefore, human H‐ferritin (HFn), regorafenib, and Cu2+ are rationally designed as a brain‐targeted nanoplatform (HFn‐Cu‐REGO NPs), fulfilling the task of site‐specific delivery and manipulating autophagy and cuproptosis against GBM. Herein, HFn affords a preferential accumulation capacity to GBM due to transferrin receptor 1 (TfR1)‐mediated active targeting and pH‐responsive delivery behavior. Moreover, regorafenib can inhibit autophagosome‐lysosome fusion, resulting in lethal autophagy arrest in GBM cells. Furthermore, Cu2+ not only facilitates the encapsulation of regorafenib to HFn through coordination interaction but also disturbs copper homeostasis for triggering cuproptosis, resulting in a synergistical effect with regorafenib‐mediated lethal autophagy arrest against GBM. Therefore, this work may broaden the clinical application scope of Cu2+ and regorafenib in GBM treatment via modulating autophagy and cuproptosis.

AuPt-Loaded Cu-Doped Polydopamine Nanocomposites with Multienzyme-Mimic Activities for Dual-Modal Imaging-Guided and Cuproptosis-Enhanced Photothermal/Nanocatalytic Therapy

“…It is distinct from the existing programmed cell death modalities such as apoptosis, necrosis, pyroptosis, and ferroptosis. Cuproptosis depends on the excessive accumulation of Cu 2+ in tumor cells . In detail, when Cu 2+ entered into tumor cells, it would bind to dihydrolipoamide S-acetyltransferase (DLAT) and lead to the aggregation of lipoylated DLAT.…”

Cell death mediated by nanotechnology via the cuproptosis pathway: A novel horizon for cancer therapy

“…Reproduced with permission. 41,42,44,49 Copyright 2022, Wiley-VCH. thus demonstrating excellent tumor inhibition ability (tumor inhibition rate: 56%).…”

“…Recently, a variety of endogenous stimulus-responsive nanomaterials have been designed to respond to certain unique features in the tumor microenvironment, such as hypoxia, acidic pH, high ROS, overexpressed enzymes, and enriched GSH, for improving the selectivity and specificity of cancer treatment. 43 For example, Zhang and coworkers 44 developed a pH-responsive nano-delivery system (HFn-Cu-regorafenib (REGO) NPs) consisting of human H-ferritin (HFn), chemotherapeutic agent regorafenib and Cu 2+ to induce autophagy and cuproptosis for glioblastoma treatment (Figure 5A). Benefiting from the modification of HFn, HFn-Cu-REGO NPs showed good blood-brain barrier permeation, tumor-site accumulation, and pH-responsive disassembly capability.…”

Cell death mediated by nanotechnology via the cuproptosis pathway: a novel horizon for cancer therapy

“…developed a pH-responsive nano-delivery system (HFn-Cu-REGO NPs) consisting of human H-ferritin (HFn), chemotherapeutic agent regorafenib and Cu 2+ to induce autophagy and cuproptosis for glioblastoma treatment (Figure 4A ). 44 Benefiting from the modification of HFn, HFn-Cu-REGO NPs showed good bloodbrain barrier (BBB) permeation, tumor-site accumulation, and pH-responsive disassembly capability. Upon treatment with HFn-Cu-REGO NPs, the pH-responsive nano-delivery system was responsive disassembled and released regorafenib and Cu 2+ in response to the acidic pH, causing concentrations of regorafenib and Cu 2+ was locally elevated in tumor region.…”