RNA nanomed最新文献

{"title":"Harnessing Computational Approaches for RNA-Targeted Drug Discovery.","authors":"Yuanzhe Zhou, Shi-Jie Chen","doi":"10.59566/isrnn.2024.0101001","DOIUrl":"https://doi.org/10.59566/isrnn.2024.0101001","url":null,"abstract":"<p><p>RNA molecules have emerged as promising therapeutic targets due to their diverse functional and regulatory roles within cells. Computational modeling in RNA-targeted drug discovery presents a significant opportunity to expedite the discovery of novel small molecule compounds. However, this field encounters unique challenges compared to protein-targeted drug design, primarily due to limited experimental data availability and current models' inability to adequately address RNA's conformational flexibility during ligand recognition. Despite these challenges, several studies have successfully identified active RNA-targeting compounds using structure-based approaches or quantitative structure-activity relationship (QSAR) models. This review offers an overview of recent advancements in modeling RNA-small molecule interactions, emphasizing practical applications of computational methods in RNA-targeted drug discovery. Additionally, we survey existing databases that catalog nucleic acid-small molecule interactions. As interest in RNA-small molecule interactions grows and curated databases expand, the field anticipates rapid development. Novel computational models are poised to enhance the identification of potent and selective small-molecule modulators for therapeutic needs.</p>","PeriodicalId":520473,"journal":{"name":"RNA nanomed","volume":"1 1","pages":"1-15"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conversion of Chemical Drugs into Targeting Ligands on RNA Nanoparticles and Assessing Payload Stoichiometry for Optimal Biodistribution in Cancer Treatment.","authors":"Congcong Xu, Hongran Yin, Tesla Yudhistira, Zhefeng Li, Daniel W Binzel, Peixuan Guo","doi":"10.59566/isrnn.2024.0101109","DOIUrl":"10.59566/isrnn.2024.0101109","url":null,"abstract":"<p><p>Active targeting-mediated nanodelivery takes advantages of ligand-receptor specificity to avoid non-specific distribution, holding great promise for the treatment of a spectrum of diseases. RNA nanoparticles have demonstrated rapid spontaneous tumor targeting and very little organ accumulation due to rapid renal clearance of non-tumor accumulated RNA nanoparticles. However available ligands for specific cells are limited, yet many chemical entities possess receptor targeting capability and remains unexplored. To provide specific tumor accumulation, a multivalent targeting strategy on RNA nanoparticles to control their <i>in vivo</i> fate is implemented. Methotrexate (MTX), a clinically approved chemotherapy was used as a tumor-targeting ligand through conjugation to our RNA nanoparticle with controlled conjugation of various copy numbers. As copies of conjugated MTX increased on the nanoparticle, the specific binding to overexpressed folate receptor was enhanced as demonstrated by flow cytometry analysis and confocal microscopy imaging. Increasing the amounts of conjugated MTX did not significantly change the nanoparticle size, Zeta potential, or cytokine induction. Increased amounts of conjugated MTX resulted in improved cell inhibition due to MTX release following cell internalization. However, increasing conjugated MTX to the RNA nanoparticles reduced the melting temperature of RNA nanoparticles and increased <i>in vitro</i> serum protein binding to the nanoparticles. Thus, <i>in vivo</i> biodistribution profiles of RNA nanoparticles revealed different behaviors based on MTX conjugation in cancer targeting and clearance. Increased copies of MTX changed the ability of nanoparticles to target tumors, accumulate in healthy organs, and rapidly clear through the urine. Nanoparticle design must be closely considered for optimized cancer targeting and therapy, providing the rationale for a proper design of RNA nanodelivery in cancer treatment.</p>","PeriodicalId":520473,"journal":{"name":"RNA nanomed","volume":"1 1","pages":"109-123"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted Delivery of Potent Chemical Drugs and RNAi to Drug-Resistant Breast Cancer Using RNA-Nanotechnology and RNA-Ligand Displaying Extracellular vesicles.","authors":"Yuan Soon Ho, Tzu-Chun Cheng, Peixuan Guo","doi":"10.59566/isrnn.2024.0101016","DOIUrl":"10.59566/isrnn.2024.0101016","url":null,"abstract":"<p><p>This review describes a new technology to treat breast-cancer-drug-resistance by targeting the ABC as the multi-homo-subunit ATPase, enlightening by the Christmas-lighting budge with serial circuit and the asymmetrical homo-hexamer of the phi29 DNA packaging motor with sequential revolving mechanism. Chemotherapeutics has been widely used in breast cancer treatments, but drug resistance has raised a serious concern. RNA therapeutics has emerged as the third milestone in pharmaceutical drug development. RNA nanoparticles are dynamic, mild, and deformative, resulting in spontaneous, rapid, and efficient accumulation in tumor vasculature after IV injection. Their negative charge and favorable size bypass the nonspecific targeting of vital organs and normal cells. This motile and deformable nature also led to the fast passing of glomerular filters and their movement into the urine for rapid body clearance for those non-tumor-accumulated nanoparticles, resulting in undetectable toxicity. Extracellular vesicles have shown potential as a delivery system for RNAi and chemotherapeutic drugs <i>in vivo</i>, contributing to the efficacy of cancer remission. However, the lack of cell-targeting ligands on extracellular vesicles and the nonspecific entry into healthy cells has led to safety concerns. This review addresses how to apply RNA nanotechnology and RNA-ligand displaying extracellular vesicles for specific delivery to breast cancer. The particular focus is on using and combining the RNA and extracellular vesicle technology to deal with breast cancer drug resistance. The targeting capabilities and drug safety can be improved through extracellular vesicle engineering techniques, such as affixing ligands on the extracellular vesicle surface utilizing arrow-tail RNA nanoparticles, ultimately addressing off-target effects and toxicity. Using RNA ligands for specific targeting and the efficient membrane fusion of extracellular vesicles has enabled the development of ligand-displayed extracellular vesicles capable of delivering both RNAi and chemical drugs to cells with precision, effectively inhibiting tumor growth. The negative charge inherent in the vesicles results in electrostatic repulsion, reducing non-specific binding to healthy cells that contain negatively charged lipid membranes. By leveraging the principles of RNA nanotechnology, the engineering of extracellular vesicles offers a promising avenue for addressing breast cancer drug resistance. This review also discusses applying the series of circuit mechanisms in Christmas-decorating-lighting to develop effective therapeutics to combat breast cancer chemoresistance by targeting the ABC drug transporter and breast cancer surface receptors.</p>","PeriodicalId":520473,"journal":{"name":"RNA nanomed","volume":"1 1","pages":"16-43"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"pH-responsive bond as a linker for the release of chemical drugs from RNA-drug complexes in endosome or lysosome.","authors":"Piotr Rychahou, Sijin Guo, Yinan Zhang, Nicole Rychagov, Yekaterina Y Zaytseva, Heidi L Weiss, B Mark Evers, Peixuan Guo","doi":"10.59566/isrnn.2024.0101091","DOIUrl":"10.59566/isrnn.2024.0101091","url":null,"abstract":"<p><p>Emerging phenomena have signaled that RNA therapeutics will be the third milestone in pharmaceutical drug development. RNA nanoparticles display motile and deformable properties that lead to (1) fast and efficient tumor accumulation via both spontaneous and active targeting, and (2) fast renal excretion of non-tumor-accumulated nanoparticles due to RNA's negative charge and dynamic property; thus, undetectable toxicity. Here, we report the use of RNA nanoparticles to harbor the cancer-targeting ligand and chemical drugs and the design of the pH-responsive bond as a linker for the release of chemical drugs from RNA-drug complexes in endosomes or lysosomes. RNA nanoparticles constructed from a three-way junction (3WJ) core of bacteriophage phi29 packaging RNA (pRNA) offer an advanced strategy for receptor-selective drug delivery into cancer cells and has the potential to enhance the efficacy of anti-cancer therapies while mitigating dose-limiting toxicity in patients with colorectal cancer (CRC). We investigated conjugation of small-molecule drugs targeting the PI3K/mTOR pathway to 3WJ RNA nanoparticles and confirmed intracellular drug delivery by 3WJ RNA nanoparticles into CRC cells. 3WJ a, a single strand of 3WJ nanoparticle, was constructed with a pH-sensitive linkage conjugated to a dual PI3K/mTOR inhibitor, PI-103-azide. We demonstrated PI-103 conjugation to RNA under normal physiologic pH conditions and rapid pH-dependent drug release in an acidic environment. Next, we assembled FA-3WJ-PI103 nanoparticles from three single-stranded RNA, 3WJ a-PI-103, 3WJ b and 3WJ c-folate, to specifically target folate receptor alpha (FRα). Our tests demonstrated receptor-mediated uptake of FA-pRNA-PI-103 nanoparticles, pH-responsive PI-103 drug release from lysosomes and inhibition of the PI3K/mTOR pathway in CRC cells and tumor spheroids. These results confirm receptor-mediated cytosolic drug delivery by pH-responsive RNA nanoparticles and demonstrate potential of the 3WJ-drug complex as a novel strategy for receptor-selective drug delivery to cancer cells with high FRα expression.</p>","PeriodicalId":520473,"journal":{"name":"RNA nanomed","volume":"1 1","pages":"91-108"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}