Glycoscience in Advancing PD-1/PD-L1-Axis-Targeted Tumor Immunotherapy DOI Open Access
Qianqian Sun, Senlian Hong

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(3), С. 1238 - 1238

Опубликована: Янв. 31, 2025

Immune checkpoint blockade therapy, represented by anti-PD-1/PD-L1 monoclonal antibodies, has significantly changed the immunotherapy landscape. However, treatment is still limited unsatisfactory response rates, immune-related adverse effects, and drug resistance. Current studies have established that glycosylation, a common post-translational modification, crucial in promoting cancer progression immune invasion. Targeting aberrant glycosylation cancers presents precision medicine regimens for monitoring developing personalized medicine. Notably, checkpoints PD-1 PD-L1 are highly glycosylated, which affects PD-1/PD-L1 interaction binding of antibodies. Recent achievements glycoscience to enhance patient outcomes, referred as glycotherapy, underscored their high potency advancing therapies, i.e., glycoengineered antibodies with improved toward PD-1/PD-L1, pharmaceutic inhibitors core fucosylation sialylation, synergistic antibody-sialidase conjugate. This review briefly introduces axis highlights fundamental applied advances improve immunoblockade therapies.

Язык: Английский

Enzyme Core Spherical Nucleic Acid That Enables Enhanced Cuproptosis and Antitumor Immune Response through Alleviating Tumor Hypoxia DOI
Yuting Huang, Xueliang Liu, Jiawei Zhu

и другие.

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(20), С. 13805 - 13816

Опубликована: Март 29, 2024

Cuproptosis, a copper-dependent cell death process, has been confirmed to further activate the immune response and mediate resistance. However, hypoxic tumor microenvironment hampers cuproptosis sensitivity suppresses body's antitumor response. Herein, we have successfully immobilized functionalized catalase (CAT) with long single-stranded DNA containing polyvalent CpG sequences through rolling circle amplification (RCA) techniques, obtaining an enzyme-cored spherical nucleic acid nanoplatform (CAT-ecSNA-Cu) deliver copper ions for cuproptosis. The presence of long-stranded DNA-protected CAT enhances mitochondrial respiration by catalyzing conversion H2O2 O2, thereby sensitizing Meanwhile, increased oxygenation expression hypoxia-inducible factor-1 (HIF-1) protein, resulting in alleviation immunosuppressive microenvironment. Of note, induces immunogenic (ICD), which facilitates dendritic (DC) maturation antigen presentation polyCpG-supported Toll-like receptor 9 (TLR9) activation. Furthermore, cuproptosis-induced PD-L1 upregulation cells complements checkpoint blockers (αPD-L1), enhancing immunity. strategy cuproptosis-mediated responses alleviating hypoxia effectively promotes activation proliferation effector T cells, ultimately leading long-term immunity against cancer.

Язык: Английский

Процитировано

39
Polyvalent Aptamer Nanodrug Conjugates Enable Efficient Tumor Cuproptosis Therapy Through Copper Overload and Glutathione Depletion DOI
Shuang Wang, Xueliang Liu,

Dali Wei

и другие.

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(44), С. 30033 - 30045

Опубликована: Окт. 28, 2024

Cuproptosis, a recently identified form of copper-dependent cell death, shows promising tumor suppressive effects with minimal drug resistance. However, its therapeutic efficacy is hampered by dependence on copper ions and the glutathione (GSH)-rich microenvironment in tumors. Here, we have developed polyvalent aptamer nanodrug conjugates (termed CuPEs@PApt) nucleosome-like structure to improve cuproptosis therapy exploiting mitochondrial overload GSH depletion. Polyvalent (PApt), comprising epithelial adhesion molecule aptamers for targeting repetitive PolyT sequences chelation, facilitates efficient loading targeted delivery peroxide-Elesclomol nanodots (CuPEs). Upon internalization cells, Elesclomol released from CuPEs@PApt accumulates mitochondria initiate cuproptosis, while lysosomal degradation CuP generates exogenous Cu2+ H2O2, triggering Fenton-like reaction depletion enhance cuproptosis. In vitro vivo experiments confirm this strategy inducing immunogenic latter contributing activation antitumor immune response synergistic growth inhibition.

Язык: Английский

Процитировано

14
Inhibitors of Immune Checkpoints: Small Molecule- and Peptide-Based Approaches DOI Open Access
Natalie Fuchs, Longfei Zhang, Laura Calvo‐Barreiro

и другие.

Journal of Personalized Medicine, Год журнала: 2024, Номер 14(1), С. 68 - 68

Опубликована: Янв. 4, 2024

The revolutionary progress in cancer immunotherapy, particularly the advent of immune checkpoint inhibitors, marks a significant milestone fight against malignancies. However, majority clinically employed inhibitors are monoclonal antibodies (mAbs) with several limitations, such as poor oral bioavailability and immune-related adverse effects (irAEs). Another major limitation is restriction efficacy mAbs to subset patients, which triggered extensive research efforts identify alternative approaches targeting checkpoints aiming overcome restricted mAbs. This comprehensive review aims explore cutting-edge developments checkpoints, focusing on both small molecule- peptide-based approaches. By delving into drug discovery platforms, we provide insights diverse strategies optimize molecules peptides checkpoints. In addition, discuss recent advances nanomaterials carriers, providing basis for development platforms immunotherapy. Ongoing focused peptide-inspired agents paves way developing orally bioavailable next-generation immunotherapies.

Язык: Английский

Процитировано

12
Lysosome Targeting Chimaeras for Glut1-Facilitated Targeted Protein Degradation DOI

Jinyan Luo,

Quan Gao,

Kui Tan

и другие.

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(26), С. 17728 - 17737

Опубликована: Июнь 20, 2024

Targeted protein degradation technology holds great potential in biomedicine, particularly treating tumors and other protein-related diseases. Research on intracellular using molecular glues PROTAC is leading, while research the of membrane proteins extracellular through lysosomal pathway still preclinical stage. The scarcity useful targets an immense limitation to technological advancement, making it essential explore novel, potentially effective approaches for targeted degradation. Here, we employed glucose transporter Glut1 as innovative lysosome-targeting receptor devised Glut1-Facilitated Lysosomal Degradation (GFLD) strategy. We synthesized ligands via reversible addition-fragmentation chain transfer (RAFT) polymerization acquired antibody-glycooligomer conjugates bioorthogonal reactions molecules, utilized management PD-L1 high-expressing triple-negative breast cancer. a exhibits advancement broader array medications future.

Язык: Английский

Процитировано

10
Emerging Trends in DNA Nanotechnology-Enabled Cell Surface Engineering DOI Creative Commons
Fan Xiao,

Xuechu Shen,

Wenqi Tang

и другие.

JACS Au, Год журнала: 2025, Номер 5(2), С. 550 - 570

Опубликована: Фев. 6, 2025

Cell surface engineering is a rapidly advancing field, pivotal for understanding cellular physiology and driving innovations in biomedical applications. In this regard, DNA nanotechnology offers unprecedented potential precisely manipulating functionalizing cell surfaces by virtue of its inherent programmability versatile functionalities. Herein, Perspective provides comprehensive overview emerging trends engineering, focusing on key nanostructure-based tools, their roles regulating physiological processes, We first discuss the strategies integrating molecules onto surfaces, including attachment oligonucleotides higher-order nanostructure. Second, we summarize impact DNA-based various such as membrane protein degradation, signaling transduction, intercellular communication, construction artificial components. Third, highlight applications DNA-engineered targeted therapies cancer inflammation, well capture/protection diagnostic detection. Finally, address challenges future directions nanotechnology-based engineering. This aims to provide valuable insights rational design contributing development precise personalized medicine.

Язык: Английский

Процитировано

2
Polysaccharides from traditional Chinese medicine and their nano-formulated delivery systems for cancer immunotherapy DOI

Linlin Sun,

Yuting Liu, Qihui Sun

и другие.

Carbohydrate Polymers, Год журнала: 2025, Номер 357, С. 123416 - 123416

Опубликована: Фев. 20, 2025

Язык: Английский

Процитировано

2
Multivalent RGD Peptide-Mediated Nanochimera for Lysosomal Degradation of PDL1 Protein DOI

Yanfei Song,

Linjie Cui,

Zhilin Liu

и другие.

Nano Letters, Год журнала: 2025, Номер unknown

Опубликована: Фев. 27, 2025

The development of immune checkpoint inhibitors, especially PDL1 antibodies, has revolutionized cancer therapy, but the posttherapy recycling proteins poses a significant challenge by inducing resistance and reducing treatment efficacy. To address this, we introduce an integrin-driven, lysosome-targeted nanochimera, composed poly(glutamic acid), RGD peptides, is designed to engage target protein, with αvβ3 integrin binding multivalent peptides direct complex through endocytosomal pathway lysosome, ensuring degradation blocking its recycling. Our in vitro vivo experiments demonstrate that these nanochimeras potently activate T-cell antitumor immunity downregulating expression within tumor cells tissues, significantly enhancing efficacy antibodies. A key discovery our study pivotal role facilitating protein degradation, providing valuable insights for more efficacious sophisticated immunotherapies.

Язык: Английский

Процитировано

1
Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway DOI
Zhijie Wang, L. Yuan,

Xiaotong Liao

и другие.

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(8), С. 6027 - 6043

Опубликована: Апрель 10, 2024

Targeting the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has evolved into one of most promising strategies for tumor immunotherapy. Thus far, multiple monoclonal antibody drugs have been approved treating a variety tumors, while development small-molecule PD-1/PD-L1 inhibitors lagged far behind, with only few entering clinical trials. In addition to and inhibitors, reducing expression levels PD-L1 attracted extensive research interest as another strategy target pathway. Herein, we analyze structures mechanisms molecules that reduce classify them degraders downregulators according whether they directly bind PD-L1. Moreover, discuss potential prospects developing PD-L1-targeting based on these molecules. It is hoped this perspective will provide profound insights discovery potent antitumor immunity drugs.

Язык: Английский

Процитировано

9
Intelligent Modular DNA Lysosome-Targeting Chimera Nanodevice for Precision Tumor Therapy DOI

Meirong Cui,

Dan Zhang, Xian Zheng

и другие.

Journal of the American Chemical Society, Год журнала: 2024, Номер unknown

Опубликована: Окт. 20, 2024

Lysosome targeting chimeras (LYTACs) have emerged as a powerful modality that can eliminate traditionally undruggable extracellular tumor-related pathogenic proteins, but their low bioavailability and nonspecific distribution significantly restrict efficacy in precision tumor therapy. Developing LYTAC system selectively target tissues enable modular design is crucial challenging. We here report programmable nanoplatform for tumor-specific degradation of multipathogenic proteins using an intelligent DNA (IMTAC) nanodevice. employ circular origami to integrate predesigned multitarget protein binding sites pH-responsive promoters specifically recognize cell-surface lysosome-shuttling receptors tissues. By precisely manipulating the stoichiometry modularity ligands diverse IMTAC nanodevice enables accurate localization delivery into tissues, where acidic microenvironment triggers switch activation, multivalent binding, efficient various prespecified proteins. The tissue-specificity multiple IMTACs improve drug utilization rate while reducing off-target effects. Importantly, this demonstrates capability collabo-rative EGFR PDL1 tissue combined immunity therapy hepatocellular carcinoma (HCC), resulting obvious necrosis inhibition growth vivo even at concentrations. This study presents unique strategy building general, intelligent, modular, simple encoded designing medicine degraders developing proprietary antitumor drugs.

Язык: Английский

Процитировано

9
Polyvalent Aptamer-Functionalized NIR-II Quantum Dots for Targeted Theranostics in High PD-L1-Expressing Tumors DOI
Xin Huang, Jiawei Zhu,

Chuhuang Dong

и другие.

ACS Applied Materials & Interfaces, Год журнала: 2024, Номер 16(17), С. 21571 - 21581

Опубликована: Апрель 18, 2024

Ag2S quantum dots (QDs) show superior optical properties in the NIR-II region and display significant clinical potential with favorable biocompatibility. However, inherent defects of low targeting poor solubility necessitate practical modification methods to achieve theranostics QDs. Herein, we used rolling circle amplification (RCA) techniques obtain long single-stranded DNA containing PD-L1 aptamer C-rich palindromic sequence. The sequences can specifically chelate Ag2+ thus serve as a template result biomimetic mineralization formation pApt-Ag2S These QDs enable specific illuminate hot tumors high expression effectively, serving excellent molecular targeted probes. In addition, due absorption QDs, exhibit remarkable photothermal properties. And besides, polyvalent aptamers recognize protein effectively block inhibitory signal on T cells, enabling efficient through synergistic effect therapy immune checkpoint blocking therapy. Summary, enhance biological stability antibleaching ability using template, thereby establishing theranostic platform that targets high-expressing inflamed demonstrates performance both vitro vivo.

Язык: Английский

Процитировано

8