Lysosomal Rupture‐Mediated “Broken Window Effect” to Amplify Cuproptosis and Pyroptosis for High‐Efficiency Cancer Immunotherapy

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: 34(29)

Published: Feb. 23, 2024

Abstract Autophagy, a lysosome‐involved degradation pathway, as self‐protective cellular process, always weakens the efficiency of tumor therapies. Herein, for first time, biodegradable copper (Cu) ions doped layered double hydroxide (Cu‐LDH) nanoparticles are reported cancer immunotherapy via lysosomal rupture‐mediated “Broken Window Effect”. Only injection Cu‐LDH single therapeutic agent achieves various organelles destruction after rupture, well abnormal aggregation Cu in cells cuproptosis and pyroptosis. More importantly, autophagy inhibition caused by rupture improves overload‐mediated pyroptosis blocking lysosome‐mediated bulk leading to good anti‐tumor immune responses ultimately high‐efficiency growth inhibition. This Effect” provides new paradigm enhanced therapy.

Language: Английский

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Nano-PROTACs: state of the art and perspectives

Nanoscale, Journal Year: 2024, Volume and Issue: 16(9), P. 4378 - 4391

Published: Jan. 1, 2024

Schematic illustration of the combinational strategy nanotechnology and PROTACs (Nano-PROTACs): typical shortcomings traditional nanotechnology-based strategies for PROTAC drugs optimization.

Language: Английский

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Thermal Proteome Profiling Strategy Identifies CNPY3 as a Cellular Target of Gambogic Acid for Inducing Prostate Cancer Pyroptosis

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(12), P. 10005 - 10011

Published: March 21, 2024

There is an urgent requirement to acquire a comprehensive comprehension of novel therapeutic targets for prostate cancer facilitate the development medications with innovative mechanisms. In this study, we identified gambogic acid (GBA) as specific pyroptosis inducer in prostatic cells. By using thermal proteome profiling (TPP) strategy, revealed that GBA induces by directly targeting canopy FGF signaling regulator (CNPY3), which was previously considered "undruggable". Moreover, through utilization APEX2-based proximity labeling method, found recruited delactatease SIRT1, resulting elimination lysine lactylation (Kla) on CNPY3. Of note, SIRT1-mediated delactylation influenced cellular localization CNPY3 promote lysosome rupture triggering pyroptosis. Taken together, our study distinctive target induction and its potential application therapy.

Language: Английский

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Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 17, 2025

Drug resistance is a common challenge in clinical tumor treatment. A reduction drug sensitivity of cells often accompanied by an increase autophagy levels, leading to autophagy-related resistance. The effectiveness combining chemotherapy drugs with inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected various types autophagy. Therefore, ferroptosis have crosstalk via autophagy, potentially switch cell death under certain conditions. As two forms inflammatory programmed death, different effects on inflammation, cGAS-STING signaling pathway also involved. it plays important role progression some chronic diseases. This review discusses relationship between pyroptosis, attempts uncover reasons behind evasion nature

Language: Английский

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Biomaterials Elicit Pyroptosis Enhancing Cancer Immunotherapy

Advanced Functional Materials, Journal Year: 2023, Volume and Issue: 34(7)

Published: Nov. 5, 2023

Abstract Cancer immunotherapy has the potential to revolutionize treatment of malignant tumors, but its effectiveness is limited by low immune response rate and immune‐related adverse events. Pyroptosis, as an inflammatory programmed cell death type, triggers strong acute antitumor immunity, converting “cold” tumors “hot”. Particularly, biomaterials loading pyroptosis inducers targeting tumor microenvironment engineer pyroptosis, have achieved great progress in recent years. Herein, design strategy, mechanism pathway, role induce cancer are comprehensively reviewed. The present review focuses on application biomaterials‐induced immunotherapy, including nanogel, polymer prodrug, nanovesicle, mesoporous material. Additionally, synthesis a series stimuli‐responsive nanoplatforms, glutathione‐responsive, pH‐responsive, reactive oxygen species‐responsive, enzyme‐mimicking catalytic performance, described. Meanwhile, it augments multiple processes uptake, antigen presentation, T‐cell activation, expansion. Finally, perspectives pyroptosis‐mediated inflammation break through vascular basement membrane barrier achieving efficient volcanic penetration discussed. Artificial intelligence, multi‐omics analysis, anthropogenic animal models organoids presented, aiming provide guidance assistance for constructing effective controllable pyroptosis‐engineered improving immunotherapy.

Language: Английский

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Biodegradable Monometallic Aluminum as a Biotuner for Tumor Pyroptosis

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(12)

Published: Feb. 1, 2024

Pyroptosis is an effective anti-tumor strategy. However, monometallic pyroptosis biotuners have not been explored until now. Here, we discover for the first time that biodegradable Al can act as a biotuner tumor therapy. pH-sensitive nanoparticles (Al@P) are obtained by equipping polyethylene glycol-b-(poly(methyl methacrylate)-co-poly(4-vinylpyridine), which exert their effect at site without affecting normal cells. The H

Language: Английский

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Ultrasound-Activated PROTAC Prodrugs Overcome Immunosuppression to Actuate Efficient Deep-Tissue Sono-Immunotherapy in Orthotopic Pancreatic Tumor Mouse Models

Nano Letters, Journal Year: 2024, Volume and Issue: 24(28), P. 8741 - 8751

Published: July 2, 2024

The degradation of oncoproteins mediated by proteolysis-targeting chimera (PROTAC) has emerged as a potent strategy in cancer therapy. However, the clinical application PROTACs is hampered challenges such poor water solubility and off-target adverse effects. Herein, we present an ultrasound (US)-activatable PROTAC prodrug termed NP

Language: Английский

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AI-powered omics-based drug pair discovery for pyroptosis therapy targeting triple-negative breast cancer

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 30, 2024

Due to low success rates and long cycles of traditional drug development, the clinical tendency is apply omics techniques reveal patient-level disease characteristics individualized responses treatment. However, heterogeneous form data uneven distribution targets make discovery precision medicine a non-trivial task. This study takes pyroptosis therapy for triple-negative breast cancer (TNBC) as paradigm uses mining large TNBC cohort databases establish biofactor-regulated neural network rapidly screening optimizing compound pairs. Subsequently, biomimetic nanococrystals are prepared using preferred combination mitoxantrone gambogic acid rational delivery. The unique mechanism obtained regulating genes through ribosomal stress triggering cascade immune effects revealed in models. In this work, target omics-based intelligent framework explores an innovative development paradigm, which repurposes existing drugs enables precise treatment refractory diseases.

Language: Английский

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Iridium(III) Photosensitizers Induce Simultaneous Pyroptosis and Ferroptosis for Multi‐Network Synergistic Tumor Immunotherapy

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(49)

Published: Aug. 24, 2024

Abstract The integration of pyroptosis and ferroptosis hybrid cell death induction to augment immune activation represents a promising avenue for anti‐tumor treatment, but there is lack research. Herein, we developed two iridium (III)‐triphenylamine photosensitizers, IrC IrF , with the capacity disrupt redox balance induce photo‐driven cascade damage DNA Kelch‐like ECH‐associated protein 1 (KEAP1). absent in melanoma 2 (AIM2)‐related cytoplasmic nucleic acid‐sensing pathway, triggered by damaged DNA, leads gasdermin D (GSDMD)‐mediated pyroptosis. Simultaneously, iron homeostasis, regulated KEAP1/nuclear factor erythroid 2‐related (NRF2)/heme oxygenase (HO‐1) serves as pivotal bridge, facilitating not only E (GSDME)‐mediated non‐canonical pyroptosis, also synergy glutathione peroxidase 4 (GPX4) depletion. collaborative action generates synergistic effect that elicits immunogenic death, stimulates robust response effectively inhibits tumor growth vivo. Our work introduces first metal‐based small molecule dual‐inducers potent cancer immunotherapy, highlights significance homeostasis vital hub connecting effects ferroptosis.

Language: Английский

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Proteolysis-targeting drug delivery system (ProDDS): integrating targeted protein degradation concepts into formulation design

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(19), P. 9582 - 9608

Published: Jan. 1, 2024

Targeted protein degradation (TPD) has emerged as a revolutionary paradigm in drug discovery and development, offering promising avenue to tackle challenging therapeutic targets. Unlike traditional approaches that focus on inhibiting function, TPD aims eliminate proteins of interest (POIs) using modular chimeric structures. This is achieved through the utilization proteolysis-targeting chimeras (PROTACs), which redirect POIs E3 ubiquitin ligases, rendering them for by cellular ubiquitin-proteasome system (UPS). Additionally, other technologies such lysosome-targeting (LYTACs) autophagy-based degraders facilitate transportation endo-lysosomal or autophagy-lysosomal pathways degradation, respectively. Despite significant growth preclinical research, many fail progress beyond this stage development. Various factors contribute limited success agents, including hurdle inadequate delivery target site. Integrating into platforms could surmount challenges

Language: Английский

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