Erythrocyte Membrane Camouflaged Metal–Organic Framework Nanodrugs for Remodeled Tumor Microenvironment and Enhanced Tumor Chemotherapy

Abstract

The abundant extracellular matrix (ECM) in solid tumors causes limited drug penetration and hypoxia-mediated chemoresistance, which lead to poor chemotherapy outcomes. To solve this problem, a biomimetic metal-organic framework nanodrug (ZIF-8-DOX-LY-RM) is developed with red blood cell membrane (RM) camouflage and encapsulation of type 1 transforming growth factor β receptor (TGFBR1) inhibitor and doxorubicin (DOX) for efficient chemotherapy. Based on the biomimetic properties of the erythrocyte membrane, ZIF-8-DOX-LY-RM can effectively accumulate in tumor tissues with immune escape and prolonged blood circulation. Then, the enriched nanodrug ZIF-8-DOX-LY-RM releases the TGFBR1 to remove collagen, subsequently leading to enhanced nanodrug penetration and increased oxygen supply. The abundant oxygen supply then relieves hypoxia-mediated chemoresistance of DOX through increased cellular uptake and elevated reactive oxygen species production. The in vivo studies demonstrate the outstanding performance of ZIF-8-DOX-LY-RM nanoparticles in chemotherapy of cancer. This work presents an ECM normalization strategy for the synergistic collagen depletion and hypoxia alleviation and opens a promising avenue for effective chemotherapy of solid tumors.

Anti-EpCAM Functionalized I-131 Radiolabeled Biomimetic Nanocarrier Sodium/Iodide-Symporter-Mediated Breast-Cancer Treatment

“…Their platform successfully delivered oxygen to reduce hypoxia by increasing the tumor-area oxygenation levels from 1.6% to 24% 24 h post-injection, enhancing radiotherapy treatment efficacy [ 40 ]. Furthermore, RBCm was used to coat metal-organic NP utilizing a TGF-β-blocking strategy, successfully reducing the extracellular matrix barrier and reducing hypoxia to enable nanocarrier penetration and overcome drug resistance [ 41 ]. Recently, a hemoglobin oxygen-carrier blood surrogate comprising a hemoglobin-loaded PLGA nanoparticle coated with nanozymes to prevent oxidation and coated with RBCm was shown to successfully preserve oxygen, and exhibited good antioxidant and stealth properties [ 42 ].…”

Nanoscale Zeolitic Imidazolate Framework (ZIF)–8 in Cancer Theranostics: Current Challenges and Prospects

“…Targeting ligand modification on the ZIF–8 surface achieved active delivery to tumor cells, and common ligands included HA, lactobionic acid (LA) [ 14 ], folic acid (FA) [ 15 ], and Arg–Gly–Asp (RGD) peptide [ 16 ]. In addition, long–time blood circulation and immune escape can also be realized by bionic mineralization on the nanodrug surface, such as coating the cancer cell or erythrocyte membrane [ 17 , 18 , 19 ]. However, existing studies have not paid enough attention to the properties of ZIF–8 itself, including the underlying mechanisms of its effects on tumor growth and the long–term toxicity in vivo.…”

Dual-responsive nanosystem based on TGF-β blockade and immunogenic chemotherapy for effective chemoimmunotherapy

“…Hypoxia is one of the main pathological features of most solid tumor microenvironment (Wilson & Hay, 2011 ; Yang et al., 2019 ) and the hypoxia tumor cells lead to immunosuppression tumor microenvironment by accumulating immunosuppressive cells and secreting immunosuppressive factors, such as TGF-β (Yang et al., 2021 ). Besides, the ECM around tumor cells contributes to tumor hypoxia and retards the interstitial delivery of nanodrugs (Qiao et al., 2022 ). More importantly, TGF-β is the major cytokine that upregulates tumor ECM and inhibiting TGF-β can reduce collagen deposition (Qiao et al., 2022 ).…”

“…Besides, the ECM around tumor cells contributes to tumor hypoxia and retards the interstitial delivery of nanodrugs (Qiao et al., 2022 ). More importantly, TGF-β is the major cytokine that upregulates tumor ECM and inhibiting TGF-β can reduce collagen deposition (Qiao et al., 2022 ). Hence, regulating TGF-β at the hypoxia tumor microenvironment would be an efficient strategy for remodeling tumor environment to improve chemoimmunotherapy.…”