{"title":"Rational Design of DNA Nanostructures as TLR9 Agonists.","authors":"Chunfa Chen, Cheng Tian, Zhuoer Jin, Yuandong Wen, Xiaoyu Xia, Qiao Ren, Cheng Zhi Huang, Hua Zuo","doi":"10.1021/acs.biomac.5c00919","DOIUrl":null,"url":null,"abstract":"<p><p>TLR9 agonists hold significant potential in vaccine development and cancer immunotherapy. While synthetic CpG oligodeoxynucleotides (ODNs) have been employed in immunotherapies, their clinical application remains constrained by dose-limiting toxicity and metabolic instability. DNA nanotechnology provides a promising strategy for the precise modulation of ligand-TLR9 interactions. In this study, DNA nanostructure-based TLR9 agonists were rationally designed by optimizing the spatial orientation of 5'-TCG ligands based on the two DNA-binding sites revealed in the TLR9 receptor crystal structure. Fine-tuning DNA nanostructure configurations enabled controllable modulation of TLR9 activation with structural flexibility identified as a critical determinant. Notably, the oligomerization of DNA nanostructures markedly enhanced TLR9 stimulation efficacy, establishing a paradigm for the rational design of TLR9 agonists. These findings advance innovative approaches for developing next-generation immunotherapeutic agents.</p>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":" ","pages":""},"PeriodicalIF":5.4000,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomacromolecules","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acs.biomac.5c00919","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
TLR9 agonists hold significant potential in vaccine development and cancer immunotherapy. While synthetic CpG oligodeoxynucleotides (ODNs) have been employed in immunotherapies, their clinical application remains constrained by dose-limiting toxicity and metabolic instability. DNA nanotechnology provides a promising strategy for the precise modulation of ligand-TLR9 interactions. In this study, DNA nanostructure-based TLR9 agonists were rationally designed by optimizing the spatial orientation of 5'-TCG ligands based on the two DNA-binding sites revealed in the TLR9 receptor crystal structure. Fine-tuning DNA nanostructure configurations enabled controllable modulation of TLR9 activation with structural flexibility identified as a critical determinant. Notably, the oligomerization of DNA nanostructures markedly enhanced TLR9 stimulation efficacy, establishing a paradigm for the rational design of TLR9 agonists. These findings advance innovative approaches for developing next-generation immunotherapeutic agents.
期刊介绍：
Biomacromolecules is a leading forum for the dissemination of cutting-edge research at the interface of polymer science and biology. Submissions to Biomacromolecules should contain strong elements of innovation in terms of macromolecular design, synthesis and characterization, or in the application of polymer materials to biology and medicine.
Topics covered by Biomacromolecules include, but are not exclusively limited to: sustainable polymers, polymers based on natural and renewable resources, degradable polymers, polymer conjugates, polymeric drugs, polymers in biocatalysis, biomacromolecular assembly, biomimetic polymers, polymer-biomineral hybrids, biomimetic-polymer processing, polymer recycling, bioactive polymer surfaces, original polymer design for biomedical applications such as immunotherapy, drug delivery, gene delivery, antimicrobial applications, diagnostic imaging and biosensing, polymers in tissue engineering and regenerative medicine, polymeric scaffolds and hydrogels for cell culture and delivery.
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