Rigid Shell Decorated Nanodevice with Fe/H₂O₂ Supply and Glutathione Depletion Capabilities for Potentiated Ferroptosis and Synergized Immunotherapy

Abstract

The overexpressed glutathione peroxidase4 (GPX4) and insufficient H 2 O 2 in tumor cells weaken ferroptosis therapy and the elicited anticancer immune response. Herein, a rigid metal-polyphenol shell decorated nanodevice ssPPE Lap @Fe-TA is constructed to successfully overcome the drawbacks of ferroptosis therapy. The ssPPE Lap @Fe-TA consists of a rigid Fe-TA networkbased shell and disulfide-containing polyphosphoester (ssPPE) core with β-lapachone loading. The rigid Fe-TA network-based shell of ssPPE Lap @ Fe-TA enables its efficient internalization by tumor cell and then disintegrates in the acidic endosome/lysosome to initiate Fe 3+ /Fe 2+ conversion-driven ferroptosis. The ssPPE core will deplete glutathione (GSH) via the disulfidethiol exchange reaction to inactivate GPX4, and also trigger the release of β-lapachone to significantly increase intracellular H 2 O 2 and then promote Fe 3+ -mediated Fenton reaction, eventually achieving strong inhibition of tumor progression. Moreover, ssPPE Lap @Fe-TA elicites a robust systemic antitumor immune response by promoting dendritic cells (DCs) maturation and T cell infiltration, and synergizes with anti-PD-L1 antibody (a-PD-L1) to strikingly suppress 4T1 tumor growth and lung metastasis.

Recent Advances of Fe(III)/Fe(II)-MPNs in Biomedical Applications

“…Additionally, the amplified ferroptosis induced tumor cell death in an immunogenic manner, thereby promoting dendritic cell (DCs) maturation and T cell infiltration. Combined with a-PD-L1, ssPPE Lap @Fe-TA dramatically inhibited the 4T1 tumor growth and lung metastasis [ 49 ]. Not surprisingly, the therapeutic mechanism of using immunotherapy in synergy with cellular ferroptosis is another innovative strategy for applying Fe-based MPNs.…”

Recent Advances of Metal–Polyphenol Coordination Polymers for Biomedical Applications

“…Polyphenol itself can inhibit tumor growth through immunomodulation [ 4 ]. In recent years, the application of MPCP to regulate the immune system and activate immune response to kill tumors has been widely studied [ 101 , 102 , 103 , 104 , 105 ]. Wang et al constructed a vaccine for immunotherapy via in situ assembly of an EGCG-Al(III) MPCP coating on living cells [ 101 ].…”

“…Finally, the efficient individualized treatment of the tumor was realized. Meanwhile, Dai et al developed a ssPPELap@Fe-TA nanodevice with a Fe-TA shell and disulfide-containing polyphosphoester (ssPPE) core with β-lapachone loading [ 103 ]. The nanodevice induced a systemic antitumor immune response by promoting dendritic cell maturation and T-cell infiltration, and acts in concert with anti-PD-L1 antibodies to significantly inhibit 4T1 tumor growth ( Figure 12 c).…”

Liposome encapsulated polydopamine nanoparticles: Enhancing ferroptosis and activating hypoxia prodrug activity

“…The Fe ions (ferrous (Fe 2+ ) or ferric (Fe 3+ ))-mediated Fenton reaction converts endogenous H 2 O 2 into strong cytotoxicity hydroxyl radicals (•OH). The high level of •OH in the cell leads to an excess of lipid peroxide (LPO) on the cell membranes, then triggers and completes ferroptosis in tumor cells [ [7] , [8] , [9] , [10] ]. Recently, tumor therapy based on ferroptosis has a good prospect in inducing cancer cell death due to its characteristics of high tumor specificity and low systemic side effects [ [11] , [12] , [13] ].…”