MicroRNA‐Triggered Programmable DNA‐Encoded Pre‐PROTACs for Cell‐Selective and Controlled Protein Degradation DOI

Jiayin Zhan,

Xiang Li, Zhe Chuan Feng

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 9, 2024

Abstract Proteolysis‐targeting chimeras (PROTACs) have accelerated drug development; however, some challenges still exist owing to their lack of tumor selectivity and on‐demand protein degradation. Here, we developed a miR NA‐ i nitiated ssembled pre‐PRO TAC (miRiaTAC) platform that enables the activation termination target degradation in cell type‐specific manner. Using miRNA‐21 as model, engineered DNA hairpins labeled with JQ‐1 pomalidomide facilitated modular assembly DNA‐encoded pre‐PROTACs through hybridization chain reaction. This configuration promoted selective polyubiquitination BRD4 upon miR‐21 initiation, highlighting significant minimal systemic toxicity. Furthermore, incorporates photolabile groups, enabling precise optical control during assembly/disassembly, mitigating risk excessive Additionally, by introducing secondary ligand targeting CDK6, these were used scaffold for programmable active miRiaTACs containing two different warheads exact stoichiometry, orthogonal multitarget The integration near‐infrared light‐mediated photodynamic therapy an upconversion nanosystem further enhanced efficacy potent vivo anticancer activity. We anticipate miRiaTAC represents intersection between dynamic nanotechnology PROTAC, potentially expanding versatility PROTAC toolkit cancer therapy.

Language: Английский

Noncanonical Amino Acids Dictate Peptide Assembly in Living Cells DOI
Xin Liu, Binbin Hu, Zhilin Yu

et al.

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

ConspectusEmulating the structural features or functions of natural systems has been demonstrated as a state-of-the-art strategy to create artificial functional materials. Inspired by assembly and bioactivity proteins, self-assembly peptides into nanostructures represents promising approach for creating biomaterials. Conventional assembled peptide biomaterials are typically formulated in solution delivered pathological sites implementing theranostic objectives. However, this translocation entails switch from formulation conditions physiological environment raises concerns about material performance. In addition, precise efficient accumulation administered at target remains significant challenge, leading potential biosafety issues associated with off-target effects. These limitations significantly hinder progress advanced To address these concerns, past few years have witnessed development situ living new endeavor optimizing biomaterial performance benefiting advances stimuli-responsive reactions regulating noncovalent interactions. refers processes via sites. Due advantages precisely forming well-defined lesions, situ-formed assemblies integrated interesting next-generation biomedical agents.Despite great developing agents, research area still suffers limited toolkit operating under complicated conditions. Considering amino acids being incorporated backbones modified units, an acid is concern. Therefore, our laboratory intensively engaged designing discovering noncanonical (ncAAs) expand manipulating various biological Thus far, we synthesized containing ncAAs 4-aminoproline, 2-nitroimidazole alanine, Se-methionine, sulfated tyrosine, glycosylated serine, which allow us develop acid-responsive, redox-responsive, enzyme-responsive systems. Based on ncAAs, established complex self-sorting assembly, self-amplified dissipative cells optimize peptides. The resulting exhibit morphological adaptability microenvironment, contributes overcoming delivery barriers improvement targeting accumulation. utilizing developed toolkit, further created supramolecular PROTACs, antagonists, probes cancer treatment diagnosis highlight implications usage. Account, summarize journey emphasis mechanism Eventually, also provide forward conceiving prospects challenges clinical translation situ-formulated

Language: Английский

Citations

0
Sulfatase-Mediated Peroxidase-like Activity: A Chemiluminescence-Based Platform for High-Throughput Screening of Natural Inhibitors in Cancer Therapy DOI
Mengyuan Cui, Wenqing Li, Li Liu

et al.

Biosensors and Bioelectronics, Journal Year: 2025, Volume and Issue: unknown, P. 117562 - 117562

Published: May 1, 2025

Language: Английский

Citations

0
MicroRNA‐Triggered Programmable DNA‐Encoded Pre‐PROTACs for Cell‐Selective and Controlled Protein Degradation DOI
Jiayin Zhan, Xiang Li, Zhe Feng

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 9, 2024

Abstract Proteolysis‐targeting chimeras (PROTACs) have accelerated drug development; however, some challenges still exist owing to their lack of tumor selectivity and on‐demand protein degradation. Here, we developed a miR NA‐ i nitiated ssembled pre‐PRO TAC (miRiaTAC) platform that enables the activation termination target degradation in cell type‐specific manner. Using miRNA‐21 as model, engineered DNA hairpins labeled with JQ‐1 pomalidomide facilitated modular assembly DNA‐encoded pre‐PROTACs through hybridization chain reaction. This configuration promoted selective polyubiquitination BRD4 upon miR‐21 initiation, highlighting significant minimal systemic toxicity. Furthermore, incorporates photolabile groups, enabling precise optical control during assembly/disassembly, mitigating risk excessive Additionally, by introducing secondary ligand targeting CDK6, these were used scaffold for programmable active miRiaTACs containing two different warheads exact stoichiometry, orthogonal multitarget The integration near‐infrared light‐mediated photodynamic therapy an upconversion nanosystem further enhanced efficacy potent vivo anticancer activity. We anticipate miRiaTAC represents intersection between dynamic nanotechnology PROTAC, potentially expanding versatility PROTAC toolkit cancer therapy.

Language: Английский

Citations

2
Assembly‐Glued Ligands and Warheads for Hypoxia‐Activatable Supramolecular Covalent Inhibitors DOI
Binbin Hu,

Weida Qin,

Yushi Wang

et al.

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 14, 2024

Abstract Targeted covalent inhibitors are promising for drug discovery and challenged by the strict structural features target proteins to sustain proximity‐induced conjugations. Herein, an assembly‐glued strategy is reported create surface‐displayed supramolecular that leverage display‐induced proximity between noncovalent ligands warheads. The ligand warhead obtained via attaching epidermal growth factor receptor (EGFR)‐binding segment or nitroreductase (NTR)‐activated moiety bola‐amphiphilic peptides, respectively. Co‐assembling with a filler peptide glues them forms inhibitor. While associates EGFR, undergoes NTR‐induced cysteine conjugation facilitated ligand‐EGFR association. In vitro studies show reliable hypoxia‐activated inhibition of EGFR phosphorylation enhanced cytotoxicity inhibitor under hypoxic condition. addition, this also allows creating targeting without small molecular drugs, due vivo results illustrate prolonged retention its efficacy in inhibiting tumor growth. These findings demonstrate simultaneous surface display warheads assembly adhesives implementation functions, thus providing new developing future.

Language: Английский

Citations

1
Advancing Proteolysis Targeting Chimera (PROTAC) Nanotechnology in Protein Homeostasis Reprograming for Disease Treatment DOI
Mengyao Wu,

Yilan Zhao,

Chi Zhang

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(42), P. 28502 - 28530

Published: Oct. 8, 2024

Proteolysis targeting chimeras (PROTACs) represent a transformative class of therapeutic agents that leverage the intrinsic protein degradation machinery to modulate hemostasis key disease-associated proteins selectively. Although several PROTACs have been approved for clinical application, suboptimal efficacy and potential adverse side effects remain challenging. Benefiting from enhanced targeted delivery, reduced systemic toxicity, improved bioavailability, nanomedicines can be tailored with precision integrate which hold significant facilitate PROTAC (nano-PROTACs) translation effects. In this review, we provide an overview recent progress in convergence nanotechnology design, leveraging inherent properties nanomaterials, such as lipids, polymers, inorganic nanoparticles, nanohydrogels, proteins, nucleic acids, precise delivery. Additionally, discuss various categories targets insights into their translational potential, alongside challenges need addressed.

Language: Английский

Citations

1
Self-Assembly in Living Cells: Bottom-Up Syntheses in Natural Factory DOI
Na Song, Feng Tian,

Yixuan Zou

et al.

ACS Applied Materials & Interfaces, Journal Year: 2024, Volume and Issue: 16(35), P. 45821 - 45829

Published: Aug. 23, 2024

In situ self-assembly in living systems is referred to as the processes that regulate assembly by stimuli-responsive reactions at target sites under physiological conditions. Due advantages of precisely forming well-defined nanostructures pathological lesions, situ-formed assemblies with tailored bioactivity are promising for development next-generation biomedical agents. this Perspective, we summarize progress peptides cells an emphasis on state-of-the-art strategies regulating processes, establishing complexity within systems, and exploiting their applications biomedicines. We also provide our forward conceiving perspectives challenges demonstrate its great potential creating biomaterials healthcare future.

Language: Английский

Citations

0
MicroRNA‐Triggered Programmable DNA‐Encoded Pre‐PROTACs for Cell‐Selective and Controlled Protein Degradation DOI

Jiayin Zhan,

Xiang Li, Zhe Chuan Feng

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 9, 2024

Abstract Proteolysis‐targeting chimeras (PROTACs) have accelerated drug development; however, some challenges still exist owing to their lack of tumor selectivity and on‐demand protein degradation. Here, we developed a miR NA‐ i nitiated ssembled pre‐PRO TAC (miRiaTAC) platform that enables the activation termination target degradation in cell type‐specific manner. Using miRNA‐21 as model, engineered DNA hairpins labeled with JQ‐1 pomalidomide facilitated modular assembly DNA‐encoded pre‐PROTACs through hybridization chain reaction. This configuration promoted selective polyubiquitination BRD4 upon miR‐21 initiation, highlighting significant minimal systemic toxicity. Furthermore, incorporates photolabile groups, enabling precise optical control during assembly/disassembly, mitigating risk excessive Additionally, by introducing secondary ligand targeting CDK6, these were used scaffold for programmable active miRiaTACs containing two different warheads exact stoichiometry, orthogonal multitarget The integration near‐infrared light‐mediated photodynamic therapy an upconversion nanosystem further enhanced efficacy potent vivo anticancer activity. We anticipate miRiaTAC represents intersection between dynamic nanotechnology PROTAC, potentially expanding versatility PROTAC toolkit cancer therapy.

Language: Английский

Citations

0