Signal Transduction and Targeted Therapy最新文献

{"title":"Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy","authors":"Zhaorong Chen, Rayk Behrendt, Lennart Wild, Martin Schlee, Christian Bode","doi":"10.1038/s41392-025-02174-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02174-2","url":null,"abstract":"<p>Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such as acute respiratory distress syndrome, sepsis, trauma and ischemia lead to the aberrant cytosolic accumulation and massive release of nucleic acids that are detected by antiviral innate immune receptors in the endosome or cytosol. Activation of receptors for deoxyribonucleic acids and ribonucleic acids triggers inflammation, a major contributor to morbidity and mortality in critically ill patients. In the past decade, there has been growing recognition of the therapeutic potential of targeting nucleic acid sensing in critical care. This review summarizes current knowledge of nucleic acid sensing in acute respiratory distress syndrome, sepsis, trauma and ischemia. Given the extensive research on nucleic acid sensing in common pathological conditions like cancer, autoimmune disorders, metabolic disorders and aging, we provide a comprehensive summary of nucleic acid sensing beyond critical illness to offer insights that may inform its role in critical conditions. Additionally, we discuss potential therapeutic strategies that specifically target nucleic acid sensing. By examining nucleic acid sources, sensor activation and function, as well as the impact of regulating these pathways across various acute diseases, we highlight the driving role of nucleic acid sensing in critical illness.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"87 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics","authors":"Xiaofeng Dai, Yuting Fan, Xing Zhao","doi":"10.1038/s41392-025-02168-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02168-0","url":null,"abstract":"<p>Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs. Diversified types of medications have been shown effective for alleviating SLE syndromes, ranging from cytokines, antibodies, hormones, molecular inhibitors or antagonists, to cell transfusion. Drugs developed for treating other diseases may benefit SLE patients, and agents established as SLE therapeutics may be SLE-inductive. Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety. After introducing the research history of SLE and its epidemiology, we categorized primary determinants driving SLE pathogenesis by their mechanisms; combed through current knowledge on SLE diagnosis and grouped them by disease onset, activity and comorbidity; introduced the genetic, epigenetic, hormonal and environmental factors predisposing SLE; and comprehensively categorized preventive strategies and available SLE therapeutics according to their functioning mechanisms. In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"124 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting tumor-intrinsic S100 calcium-binding protein A1 augments antitumor immunity and potentiates immunotherapy efficacy","authors":"Yufeng Guo, Rui Wan, Jianchun Duan, Li Yuan, Zhijie Wang, Jia Zhong, Xue Zhang, Zixiao Ma, Hua Bai, Jie Wang","doi":"10.1038/s41392-025-02190-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02190-2","url":null,"abstract":"<p>Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but the therapeutic response is highly heterogeneous, which highlights the necessity for developing predictive biomarkers and overcoming ICB resistance. Cancer cell-intrinsic features, especially those that can be dynamically monitored via liquid biopsy, represent a broader scope for biomarker development. In addition, a potential mode of ICB resistance is tumor-intrinsic mechanisms leading to an immunosuppressive tumor microenvironment (TME). However, the underlying interactive network remains elusive, and the generalizable biomarkers and targeting strategies are still lacking. Here, we uncovered the potential of plasma S100 calcium-binding protein A1 (S100A1) for determining ICB efficacy via liquid biopsy of patients with lung cancer. Multiomics and functional studies have suggested that tumor-intrinsic S100A1 expression correlated with an immunologically “cold” TME and resistance to ICB in multiple syngeneic murine tumors and tissue samples from patients with lung cancer. Mechanistic investigations demonstrated that interfering with the tumor-intrinsic S100A1/ubiquitin-specific protease 7/p65/granulocyte-macrophage colony-stimulating factor (GM-CSF) modulatory axis could potentiate an inflamed TME by promoting M1-like macrophage polarization and T cell function. GM-CSF priming was sufficient to enhance the ICB response in tumors with high S100A1 expression in preclinical models. These findings define S100A1 as a potential blood-based biomarker and a novel synergistic target for cancer immunotherapy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"39 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monocyte-lineage tumor infiltration predicts immunoradiotherapy response in advanced pretreated soft-tissue sarcoma: phase 2 trial results","authors":"Antonin Levy, Daphné Morel, Matthieu Texier, Maria E. Rodriguez-Ruiz, Lisa Bouarroudj, Fanny Bouquet, Alberto Bustillos, Clément Quevrin, Céline Clémenson, Michele Mondini, Lydia Meziani, Roger Sun, Nadia Zaghdoud, Lambros Tselikas, Tarek Assi, Matthieu Faron, Charles Honoré, Carine Ngo, Benjamin Verret, Cécile Le Péchoux, Axel Le Cesne, Florent Ginhoux, Christophe Massard, Rastilav Bahleda, Eric Deutsch","doi":"10.1038/s41392-025-02173-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02173-3","url":null,"abstract":"<p>Immunoradiotherapy holds promise for improving outcomes in patients with advanced solid tumors, including in soft-tissue sarcoma (STS). However, the ideal combination of treatment modalities remains to be determined, and reliable biomarkers to predict which patients will benefit are lacking. Here, we report the results of the STS cohort of the SABR-PDL1 phase II trial that evaluated the anti-PDL1 atezolizumab combined with stereotactic body radiation therapy (SBRT) delivered concurrently with the 2nd cycle to at least one tumor site. Eligible patients received atezolizumab until progression or unmanageable toxicity, with SBRT at 45 Gy in 3 fractions). The primary endpoint was one-year progression-free survival (PFS) rate with success defined as 13 patients achieving 1-year PFS. Sixty-one heavily pretreated patients with STS (median 5 prior lines; 52% men; median age 54 years; 28% leiomyosarcoma) were enrolled across two centers (France, Spain). SBRT was delivered to 55 patients (90%), with the lung being the most commonly irradiated site (50%). After a median follow-up of 45 months, the one-year PFS rate was 8.3% [95% CI: 3.6–18.1]. Median PFS and overall survival were 2.5 and 8.6 months, respectively. Best responses included partial responses (5%) and stable disease (60%). Immune profiling revealed increased immunosuppressive tumor-associated macrophages (e.g., IL4I1, HES1) and monocyte-recruiting chemokines in non-responders. Higher monocyte/lymphocyte ratios (MonoLR) in tumor and blood correlated with progression. PD-L1 status, lymphoid infiltration, and tertiary-lymphoid structures were not predictive. Although the primary endpoint was not met, this study highlights MonoLR imbalance as a potential biomarker to identify STS patients likely to benefit from immunoradiotherapy. EudraCT No. 2015-005464-42; Clinicaltrial.gov number: NCT02992912.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancer transcription profiling reveals an enhancer RNA-driven ferroptosis and new therapeutic opportunities in prostate cancer","authors":"Sheng Ma, Zixian Wang, Zezhong Xiong, Yue Ge, Meng-Yao Xu, Junbiao Zhang, Yuzheng Peng, Qin Zhang, Jiaxue Sun, Zirui Xi, Hao Peng, Wenjie Xu, Yanan Wang, Le Li, Chunyu Zhang, Zheng Chao, Baojun Wang, Xu Gao, Xu Zhang, Gong-Hong Wei, Zhihua Wang","doi":"10.1038/s41392-025-02170-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02170-6","url":null,"abstract":"<p>Enhancer RNAs (eRNAs), a subclass of non-coding RNAs transcribed from enhancer regions, have emerged as critical regulators of gene expression; however, their functional roles in prostate cancer remain largely unexplored. In this study, we performed integrated chromatin accessibility and transcriptomic analyses using ATAC-seq and RNA-seq on twenty pairs of prostate cancer and matched benign tissues. By incorporating chromatin immunoprecipitation sequencing data, we identified a subset of differentially expressed eRNAs significantly associated with genes involved in prostate development and oncogenic signaling pathways. Among these, lactotransferrin-eRNA (<i>LTF</i>e) was markedly downregulated in prostate cancer tissues, with functional analyses revealing its tumor-suppressive role. Mechanistically, <i>LTF</i>e promotes the transcription of its target gene, lactotransferrin (<i>LTF</i>), by interacting with heterogeneous nuclear ribonucleoprotein F (HNRNPF) and facilitating enhancer-promoter chromatin interactions. Furthermore, we demonstrate that the <i>LTF</i>e-<i>LTF</i> axis facilitates ferroptosis by modulating iron transport. Notably, androgen receptor (AR) signaling disrupts <i>LTF</i>e-associated chromatin looping, leading to ferroptosis resistance. Therapeutically, co- administration of the AR inhibitor enzalutamide and the ferroptosis inducer RSL3 significantly suppressed tumor growth, offering a promising strategy for castration-resistant prostate cancer. Collectively, this study provides novel insights into the mechanistic role of eRNAs in prostate cancer, highlighting the <i>LTF</i>e-<i>LTF</i> axis as a critical epigenetic regulator and potential therapeutic target for improved treatment outcomes.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"124 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breaking down KRAS: small-molecule degraders for cancer therapy","authors":"Tina Kos, Dieter Saur","doi":"10.1038/s41392-025-02172-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02172-4","url":null,"abstract":"<p>In their recently published study in <i>Science</i>, Popow and colleagues developed a proteolysis-targeting chimera (PROTAC) for the in vivo degradation of several oncogenic KRAS variants.¹ Leveraging detailed biophysical analyses and crystal structures of ternary complexes of candidate ligands for KRAS and the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex, they designed a small molecule capable of potently and selectively targeting 13 of the 17 most common KRAS mutants.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"73 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PD-1 antibody camrelizumab plus apatinib and SOX as first-line treatment in patients with AFP-producing gastric or gastro-esophageal junction adenocarcinoma (CAP 06): a multi-center, single-arm, phase 2 trial","authors":"Yakun Wang, Jialin Lu, Xiaoyi Chong, Chang Wang, Xiaofeng Chen, Zhi Peng, Yanhong Gu, Yizhuo Wang, Xicheng Wang, Jian Li, Jifang Gong, Changsong Qi, Jiajia Yuan, Zhihao Lu, Ming Lu, Jun Zhou, Yanshuo Cao, Yang Chen, Cheng Zhang, Zhiguo Hou, Hongyi Kou, Lin Shen, Xiaotian Zhang","doi":"10.1038/s41392-025-02193-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02193-z","url":null,"abstract":"<p>Alpha-fetoprotein-producing gastric or gastro-esophageal junction (AFP-G/GEJ) cancer, a rare gastric cancer subtype, exhibits increased angiogenesis and more immunosuppression than non-AFP-G/GEJ cancer. The potential benefits of anti-angiogenic agents and immunotherapy for this specific subtype remain unknown. This multi-center, single-arm, phase 2 trial (ClinicalTrials.gov NCT04609176) evaluated the antitumor activity, safety, and biomarkers of camrelizumab plus apatinib and S-1 and oxaliplatin (SOX), followed by maintenance treatment with camrelizumab plus apatinib, as a first-line treatment in patients with AFP-G/GEJ adenocarcinoma. Primary endpoint was the confirmed objective response rate (ORR) per RECIST v1.1 in the full analysis set. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response, time to response, and safety. Between December 4, 2020, and August 4, 2023, 36 patients were enrolled and treated. The trial met its primary endpoint with a confirmed ORR of 66.7% (95% CI: 49.0–81.4). The DCR was 88.9% (95% CI: 73.9-96.9). With a median follow-up of 11.7 months (range: 3.2-37.9), the median PFS reached 7.8 months (95% CI: 4.9-12.3) and the median OS reached 18.0 months (95% CI: 10.5-NR). No new safety concerns were identified. In exploratory analysis, patients with durable clinical benefit exhibited higher pre-treatment (PD-1⁺) CD8⁺ T cell densities and effective scores. First-line treatment with camrelizumab plus apatinib and SOX, followed by maintenance treatment with camrelizumab plus apatinib, is effective and safe in AFP-G/GEJ adenocarcinoma. Further studies are necessary to validate these findings.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"54 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in the structures, mechanisms and targeting of molecular chaperones","authors":"Jinying Gu, Yanyi He, Chenxi He, Qiuyue Zhang, Qifei Huang, Shangjun Bai, Ruoning Wang, Qidong You, Lei Wang","doi":"10.1038/s41392-025-02166-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02166-2","url":null,"abstract":"<p>Molecular chaperones, a class of complex client regulatory systems, play significant roles in the prevention of protein misfolding and abnormal aggregation, the modulation of protein homeostasis, and the protection of cells from damage under constantly changing environmental conditions. As the understanding of the biological mechanisms of molecular chaperones has increased, their link with the occurrence and progression of disease has suggested that these proteins are promising targets for therapeutic intervention, drawing intensive interest. Here, we review recent advances in determining the structures of molecular chaperones and heat shock protein 90 (HSP90) chaperone system complexes. We also describe the features of molecular chaperones and shed light on the complicated regulatory mechanism that operates through interactions with various co-chaperones in molecular chaperone cycles. In addition, how molecular chaperones affect diseases by regulating pathogenic proteins has been thoroughly analyzed. Furthermore, we focus on molecular chaperones to systematically discuss recent clinical advances and various drug design strategies in the preclinical stage. Recent studies have identified a variety of novel regulatory strategies targeting molecular chaperone systems with compounds that act through different mechanisms from those of traditional inhibitors. Therefore, as more novel design strategies are developed, targeting molecular chaperones will significantly contribute to the discovery of new potential drugs.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"20 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thalidomide-based regimen shows promising efficacy in large granular lymphocytic leukemia: a multicenter phase II study","authors":"Ying Yu, Yuxi Li, Rui Cui, Yuting Yan, Fei Li, Yan Chen, Tingyu Wang, Xiaoli Hu, Yaqing Feng, Tengteng Yu, Yanshan Huang, Jingwen Sun, Rui Lyu, Wenjie Xiong, Qi Wang, Wei Liu, Gang An, Weiwei Sui, Yan Xu, Wenyang Huang, Dehui Zou, Huijun Wang, Zhijian Xiao, Jianxiang Wang, Lugui Qiu, Shuhua Yi","doi":"10.1038/s41392-025-02164-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02164-4","url":null,"abstract":"<p>Large granular lymphocytic leukemia (LGLL) is characterized by the clonal proliferation of cytotoxic T lymphocytes or NK cells. Standard first-line immunosuppressive treatments have limitations, achieving complete remission (CR) rates of up to 50%. Immune system dysregulation is implicated in LGLL. Promising results for thalidomide, an immunomodulatory drug, combined with prednisone and methotrexate (TPM), were observed in our pilot study. This multicenter study evaluated the efficacy and safety of a thalidomide, prednisone, and methotrexate (TPM) regimen in 52 symptomatic, methotrexate- and thalidomide-naive LGLL patients from June 2020 to August 2022. Thalidomide (100 mg daily for up to 24 months), prednisone (0.5–1.0 mg/kg every other day, tapered after 3 months), and methotrexate (10 mg/m² weekly for up to 12 months) were administered. The primary objective was to determine the CR rate. The median follow-up duration was 29.0 months (range: 4.0–42.0). Forty-seven patients (90.4%) achieved hematological and symptomatic responses. Thirty-nine patients (75.0%) achieved CR. The median time to response was 3.0 months (range: 3.0–9.0). The median progression-free survival was 40.0 months (95% confidence interval (CI): 38.0–42.0), and the median duration of response was 39.0 months (95% CI: 36.1–41.9). The most common adverse event was peripheral neuropathy (24.1%), most of which (84.6%) were grades 1–2. Four patients experienced grade ≥3 adverse events. In conclusion, the TPM regimen was an effective and safe treatment for symptomatic LGLL patients, with a particularly high CR rate. This trial was registered at www.clinicaltrials.gov (#NCT04453345).</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"207 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Landscape of small nucleic acid therapeutics: moving from the bench to the clinic as next-generation medicines","authors":"Mohan Liu, Yusi Wang, Yibing Zhang, Die Hu, Lin Tang, Bailing Zhou, Li Yang","doi":"10.1038/s41392-024-02112-8","DOIUrl":"https://doi.org/10.1038/s41392-024-02112-8","url":null,"abstract":"<p>The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored. Compared with conventional treatments, small nucleic acid therapeutics have the potential to achieve long-lasting or even curative effects via gene editing. As a result of recent technological advances, efficient small nucleic acid delivery for therapeutic and biomedical applications has been achieved, accelerating their clinical translation. Here, we review the increasing number of small nucleic acid therapeutic classes and the most common chemical modifications and delivery platforms. We also discuss the key advances in the design, development and therapeutic application of each delivery platform. Furthermore, this review presents comprehensive profiles of currently approved small nucleic acid drugs, including 11 antisense oligonucleotides (ASOs), 2 aptamers and 6 siRNA drugs, summarizing their modifications, disease-specific mechanisms of action and delivery strategies. Other candidates whose clinical trial status has been recorded and updated are also discussed. We also consider strategic issues such as important safety considerations, novel vectors and hurdles for translating academic breakthroughs to the clinic. Small nucleic acid therapeutics have produced favorable results in clinical trials and have the potential to address previously “undruggable” targets, suggesting that they could be useful for guiding the development of additional clinical candidates.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}