Integrating Proteolysis‐Targeting Chimeras (PROTACs) with Delivery Systems for More Efficient and Precise Targeted Protein Degradation DOI

Jiachan Lin,

Zirui Chen, Dan Zhang

и другие.

Macromolecular Rapid Communications, Год журнала: 2025, Номер unknown

Опубликована: Апрель 4, 2025

Targeted protein degradation (TPD) using the proteolysis-targeting chimeras (PROTACs) is emerging as a revolutionary technology, offering potential strategy for cancer treatment by inducing of overexpressed oncogenic proteins in tumors. PROTACs function recruiting E3 ligases and utilizing ubiquitin-proteasome pathway (UPS) to catalyze target proteins. Compared traditional small molecules inhibitors, exhibit enhanced selectivity, ability overcome drug resistance, traditionally deemed "undruggable". However, poor water solubility low cellular permeability significantly limit their pharmacokinetic properties, while systemic toxicity may hinder clinical application. To address these limitations, strategies that integrate with delivery systems are gaining attention. This review summarizes latest advancements various enhance vivo efficacy reduce off-target effects PROTACs, including prototype nanoparticles, covalent modification-based prodrug strategies, innovative multi-headed designs, microneedle systems, discussing design principles associated challenges. The combination potent multifunctional holds promise accelerating translation improving therapeutic treatment.

Язык: Английский

A comprehensive review on peptide-bearing biomaterials: From ex situ to in situ self-assembly DOI
Si‐Yong Qin, Jiaqi Feng, Yin‐Jia Cheng

и другие.

Coordination Chemistry Reviews, Год журнала: 2023, Номер 502, С. 215600 - 215600

Опубликована: Дек. 14, 2023

Язык: Английский

Процитировано

38
Magnetic-Manipulated NK Cell Proliferation and Activation Enhance Immunotherapy of Orthotopic Liver Cancer DOI
Han Jiang, Hao Fu, Min Tao

и другие.

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(24), С. 13147 - 13160

Опубликована: Июнь 1, 2023

The immunotherapy of deep solid tumors in the human body, such as liver cancer, still faces great challenges, especially inactivation and insufficient infiltration immune cells tumor microenvironment. Natural killer (NK) are gaining ever-increasing attention owing to their unique features expected play an important role cancer immunotherapy. However, NK severely inactivated due highly immunosuppressive intratumor microenvironment, resulting poor clinical therapeutic efficacy. Herein, we propose a mild magnetocaloric regulation approach using magnetogenetic nanoplatform MNPs@PEI-FA/pDNA (MPFD), which is synthesized by loading heat-inducible plasmid DNA (HSP70-IL-2-EGFP) on polyethyleneimine (PEI)- folic acid (FA)-modified ZnCoFe2O4@ZnMnFe2O4 magnetic nanoparticles (MNPs) promote proliferation activation tumor-infiltrating under manipulation without limitation penetration depth for orthotopic magnetothermally responsive MPFD serves magnetism-heat nanotransducer induce gene transcription IL-2 cytokine cell activation. Both vitro vivo results demonstrate that remote (∼40 °C) initiates HSP70 promoter trigger overexpression subsequent secretion, leading situ expansion through IL-2/IL-2 receptor (IL-2R) pathways prominent inhibition. This work not only evidences potential but also reveals underlying mechanism treatment nanoplatform.

Язык: Английский

Процитировано

37
Stimuli-activatable PROTACs for precise protein degradation and cancer therapy DOI
Jing Gao, Lei Yang,

Shumin Lei

и другие.

Science Bulletin, Год журнала: 2023, Номер 68(10), С. 1069 - 1085

Опубликована: Апрель 27, 2023

Язык: Английский

Процитировано

36
Melanin-Based Immunoregulatory Nanohybrids Enhance Antitumor Immune Responses in Breast Cancer Mouse Model DOI

Kangli Guo,

Zhuolong Jiao,

Xiaoyi Zhao

и другие.

ACS Nano, Год журнала: 2023, Номер 17(11), С. 10792 - 10805

Опубликована: Июнь 2, 2023

Natural melanin nanoparticles (MNPs) have demonstrated a potential for eliciting antitumor immune responses through inducing immunogenic cell death (ICD); however, the tumor microenvironment (TME) has been shown to inhibit T cell-mediated immunity. To address this challenge, we designed TME-responsive biodegradable melanin/MnOx nanohybrids via biomineralization process. Under near-infrared (NIR) light irradiation, photothermal property of triggers ICD and release tumor-associated antigens (TAAs), while Mn2+ TAAs induce dendritic (DC) maturation provoke responses. Furthermore, immunoregulatory properties themselves are exploited reshape immunosuppressive TME downregulate PD-L1 alleviation hypoxic acidic TME. Although MNPs demonstrate higher killing efficiency than in vitro due their superior effect, exhibit significantly enhanced antimetastatic effects vivo, benefiting from ability reverse immunosuppression DC maturation. Transcriptomics analysis confirmed successful activation This work presents promising approach immunomodulation-enhanced cancer therapy intrinsic nanohybrids.

Язык: Английский

Процитировано

34
The E3 ubiquitin ligases regulate PD-1/PD-L1 protein levels in tumor microenvironment to improve immunotherapy DOI Creative Commons
Bo Hou, Ting Chen, He Zhang

и другие.

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Янв. 17, 2023

The tumor microenvironment (TME) is the surrounding environment, which critical for development and progression. TME also involved in clinical intervention treatment outcomes. Modulation of useful improving therapy strategies. PD-L1 protein on cells interacts with PD-1 T cells, contributing to cell dysfunction exhaustion, blockage immune response. Evidence has demonstrated that expression PD-1/PD-L1 associated response anti-PD-1/PD-L1 cancer patients. It important discuss regulatory machinery how finely regulated cells. In recent years, studies have was governed by various E3 ubiquitin ligases TME, resistance human cancers. this review, we will role molecular mechanisms ligases-mediated regulation TME. Moreover, describe ligases-involved alters efficacy. Altogether, targeting control levels could be a potential strategy potentiate immunotherapeutic effects

Язык: Английский

Процитировано

28
PROTACs: Novel tools for improving immunotherapy in cancer DOI
Shizhe Li, Ting Chen, Jinxin Liu

и другие.

Cancer Letters, Год журнала: 2023, Номер 560, С. 216128 - 216128

Опубликована: Март 16, 2023

Язык: Английский

Процитировано

27
PROTACs: A novel strategy for cancer drug discovery and development DOI Creative Commons
Xin Han, Yi Sun

MedComm, Год журнала: 2023, Номер 4(3)

Опубликована: Май 29, 2023

Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: small molecule that binds to target protein, an E3 ligase ligand (consisting and its recruiter), chemical linker hooks first two components together. In the past 20 years, we have witnessed advancement multiple degraders into clinical trials anticancer therapies. However, one major challenges is only very limited number recruiters are currently available as targeted protein degradation (TPD), although human genome encodes more than 600 ligases. Thus, there urgent need identify additional effective TPD applications. this review, summarized existing RING-type ubiquitin their act ligands application discovery. We believe review could serve reference future development efficient cancer discovery development.

Язык: Английский

Процитировано

26
Photonic control of image-guided ferroptosis cancer nanomedicine DOI Creative Commons
Min Jun Ko, Woojung Yoo, Sunhong Min

и другие.

Coordination Chemistry Reviews, Год журнала: 2023, Номер 500, С. 215532 - 215532

Опубликована: Ноя. 10, 2023

Язык: Английский

Процитировано

26
Light‐Triggered PROTAC Nanoassemblies for Photodynamic IDO Proteolysis in Cancer Immunotherapy DOI Creative Commons
Jiwoong Choi,

Byeongmin Park,

Jung Yeon Park

и другие.

Advanced Materials, Год журнала: 2024, Номер 36(38)

Опубликована: Июнь 20, 2024

Abstract While proteolysis‐targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment via targeted protein degradation, precisely activating them in tissues and preventing uncontrolled proteolysis at off‐target sites remain challenging. Herein, a light‐triggered PROTAC nanoassembly (LPN) photodynamic indoleamine 2,3‐dioxygenase (IDO) is reported. The LPN derived from self‐assembly of prodrug conjugates, which comprise PROTAC, cathepsin B‐specific cleavable peptide linker, photosensitizer, without any additional carrier materials. In colon models, intravenously injected LPNs initially silence activity PROTACs accumulate significantly due to an enhanced permeability retention effect. Subsequently, cancer biomarker B begins trigger release active through enzymatic cleavage linkers. Upon light irradiation, cells undergo immunogenic cell death induced by therapy promote activation effector T cells, while continuous IDO degradation simultaneously blocks tryptophan metabolite‐regulated regulatory‐T‐cell‐mediated immunosuppression. Such LPN‐mediated combinatorial effectively inhibits growth, metastasis, recurrence. Collectively, this study presents promising nanomedicine, designed synergize with other immunotherapeutic modalities, more effective safer immunotherapy.

Язык: Английский

Процитировано

17
Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy DOI Creative Commons
Liuqing Yang, Ye Yang, Jing Zhang

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Окт. 18, 2024

PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into action sites. Herein, based on ultra-pH-sensitive enzyme-sensitive nanotechnology, a type polymer PROTAC conjugated pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following construction for Cyclin-dependent kinase 4 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds many treatments even immune checkpoint blockades was selected as tumor model in this study. As result, PSRNs were found maintain nanostructure (40 nm) circulation efficiently accumulated tumors via enhanced permeation retention effect. Then, they dissociated unimers (<10 response an acidic microenvironment, facilitating internalization. Eventually, CDK4/6 degrading released intracellularly cleavage cathepsin B. Importantly, led degradation target protein vitro vivo. The also augmented blockades, through upregulation programmed cell death-ligand 1 (PD-L1) expression cells suppression regulatory T proliferation microenvironment. By combination with α-PD-1, anti-tumor outcome well achieved CT26 model. Overall, our study verifies significance precise intracellular delivery introduces promising therapeutic strategy targeted treatment CRC.

Язык: Английский

Процитировано

15