Hypertoxic self-assembled peptide with dual functions of glutathione depletion and biosynthesis inhibition for selective tumor ferroptosis and pyroptosis

Abstract

Abundant glutathione (GSH) is a biological characteristic of lots of tumor cells. A growing number of studies are utilizing GSH depletion as an effective adjuvant therapy for tumor. However, due to the compensatory effect of intracellular GSH biosynthesis, GSH is hard to be completely exhausted and the strategy of GSH depletion remains challenging. Herein, we report an l-buthionine-sulfoximine (BSO)-based hypertoxic self-assembled peptide derivative (NSBSO) with dual functions of GSH depletion and biosynthesis inhibition for selective tumor ferroptosis and pyroptosis. The NSBSO consists of a hydrophobic self-assembled peptide motif and a hydrophilic peptide derivative containing BSO that inhibits the synthesis of GSH. NSBSO was cleaved by GSH and thus experienced a morphological transformation from nanoparticles to nanofibers. NSBSO showed GSH-dependent cytotoxicity and depletion of intracellular GSH. In 4T1 cells with medium GSH level, it depleted intracellular GSH and inactivated GSH peroxidase 4 (GPX4) and thus induced efficient ferroptosis. While in B16 cells with high GSH level, it exhausted GSH and triggered indirect increase of intracellular ROS and activation of Caspase 3 and gasdermin E, resulting in severe pyroptosis. These findings demonstrate that GSH depletion- and biosynthesis inhibition-induced ferroptosis and pyroptosis strategy would provide insights in designing GSH-exhausted medicines. Graphical Abstract

Biomaterials Elicit Pyroptosis Enhancing Cancer Immunotherapy

“…[ 50 ] A stealth nanocarrier, disguised as neutrophils and loaded with decitabine, delivers precise tumor immunotherapy by triggering pyroptosis through anti‐CD11b and IR82‐coupled bovine serum albumin nanoparticles [ 51 ] NSBSO is a GSH‐responsive polymer prodrug that leads to tumor cell pyroptosis and ferroptosis through GSH depletion. [ 52 ] Similarly, GSH‐responsive nanomodulator SAS/DOX@OHS‐PEG was constructed to reverse the “cold” tumor immunotherapy by simultaneously inducing ferroptosis and pyroptosis for inhibition of lung metastasis. [ 53 ] The combination of IDO inhibitors and photosensitizers in polymer prodrug NBS‐1MT is also a strategy to improve the TME with the promise of ultimately inhibiting tumor growth.…”

A MOF-Based Potent Ferroptosis Inducer for Enhanced Radiotherapy of Triple Negative Breast Cancer

“…The BSO/ZIF-8@Au was used as a template for the formation of a Fe-based metal polyphenol network (MPN) followed by hyaluronic acid (HA) modification to obtain the BSO/ZIF-8@Au@MPN@HA (BZAMH) nanohybrid. BSO, an inhibitor of γ-glutamylcysteine synthetase (γ-GCS) responsible for intracellular biosynthesis of GSH, has been found to be able to induce efficient GSH depletion for indirect inactivation of GPX4 . The MPN shell composed of iron ions and tannic acid (TA) would decompose in a tumor microenvironment (TME), and the released ferric ions (Fe 3+ ) could be reduced to redox-active Fe 2+ as an efficient ferroptosis executor since the Fe 2+ -mediated Fenton effect is significantly higher than that of Fe 3+ .…”

“…BSO, an inhibitor of γ-glutamylcysteine synthetase (γ-GCS) responsible for intracellular biosynthesis of GSH, has been found to be able to induce efficient GSH depletion for indirect inactivation of GPX4. 43 The MPN shell composed of iron ions and tannic acid (TA) would decompose in a tumor microenvironment (TME), and the released ferric ions (Fe 3+ ) could be reduced to redox-active Fe 2+ as an efficient ferroptosis executor since the Fe 2+mediated Fenton effect is significantly higher than that of Fe 3+ . 44 The inactivation of GPX4 and local generation of •OH together induces potent ferroptosis.…”

Surface-Induced Peptide Nanofibers for Selective Bacteria Trapping

“…Driven by noncovalent interactions, peptide self-assembly has received considerable attention for its wide biomedical applications including cancer and bacterial therapy, − tissue engineering, − immune modulation, , and drug delivery. − In this work, we utilized a de novo designed self-assembling peptide to construct a bacterium trapping system with high strain selectivity. As shown in Figure , the designed molecule N-K10 contains a binding domain, a linker, and a self-assembling motif.…”