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#核酸药物

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Oct 14Wed
  1. Sci Adv59

    Citron kinase activity controls alternative splicing events that drive prostate cancer growth.

    Citron (CIT) kinase drives prostate cancer growth by phosphorylating the RNA splicing regulator THRAP3, controlling its binding to pre-messenger RNA targets and producing transcripts that stimulate growth of prostate cancer cell lines, xenografts, patient-derived organoids, and PDX-derived organoids. An antisense oligonucleotide blocking THRAP3 recruitment to a CIT-dependent RNA binding site prevented production of these transcripts and inhibited growth of cell lines and PDX-derived organoids across prostate cancer stages and lineages, but not of benign cells. The work identifies CIT-mediated alternative splicing as a therapeutic strategy in treatment-resistant prostate cancer.

    Why it matters: It offers an indirect way to hit CIT kinase, for which no selective inhibitors exist, via a splicing antisense oligonucleotide.

Oct 13Tue
  1. doi.org42

    The long noncoding RNA MAPKAPK5-AS1 promotes the formation of hepatitis B virus cccDNA by modulating the expression of NABP1

    A loss-of-function screen of 1779 human lncRNAs identified 19 lncRNAs associated with HBV infection, among them MAPKAPK5-AS1 (lnc-MAAS), a host factor required for HBV infection. Lnc-MAAS participates in converting HBV relaxed circular DNA into covalently closed circular DNA and acts by modulating expression of nucleic acid binding protein 1 (NABP1). The work identifies lnc-MAAS and NABP1 as host determinants of cccDNA formation and potential targets for anti-HBV therapeutics.

Oct 7Wed
  1. biorxiv.org47

    The Spliceosome Scaffold Component BCAS2 Promotes Pancreatic Cancer Progression through Weak 5 Splice Site Dependent Splicing Regulation

    The spliceosome scaffold component BCAS2/SPF27 drives pancreatic ductal adenocarcinoma progression by regulating alternative splicing at exons with weak splice sites. BCAS2 promotes inclusion of SOS1 exon 21, activating RAC signaling, and elevated BCAS2 expression in PDAC correlates with poor patient outcomes. Splice-switching antisense oligonucleotides that skip SOS1 exon 21 suppressed PDAC proliferation and migration, pointing to a BCAS2/SOS1/RAC axis as a therapeutic vulnerability.

Sep 28Mon
  1. nature.com56

    AI-guided optimization for thermostable mRNA vaccines

    AGENT, an AI-driven framework combining high-throughput experimentation with Bayesian optimization, engineers thermostable solid-state mRNA vaccines. The formulations retained full bioactivity after 2 months at 37 °C and elicited immune responses non-inferior to fresh vaccines. Microneedle patches enabled cold-chain-free delivery in rodents and nonhuman primates.

    Why it matters: Cold-chain-free mRNA vaccines with retained bioactivity could change vaccine distribution logistics.

  2. nature.com42

    Accelerated discovery of thermostable mRNA–lipid nanoparticle vaccines using data-efficient AI

    The paper presents a data-efficient AI workflow, Bayesian optimization implemented in the AutODEx framework, for accelerating the discovery of thermostable mRNA-lipid nanoparticle vaccines. Candidate formulations were optimized toward stability, using a SARS-CoV-2 RBD sequence deposited at GenBank (OP839194). Datasets and source code are publicly released on Zenodo and GitHub.

    Why it matters: It shows an AI-driven route to thermostable mRNA-LNP vaccines, a known cold-chain bottleneck.

  3. nature.com45

    Cargo size matters when designing lipid nanoparticles for delivery of large gene editors

    Ionizable lipids screened with a gene-editor-sized messenger RNA yielded LC-1, a lipid that forms nanoparticles with a structure enhancing endosomal escape. LC-1 enabled efficient genome editing in the liver, lung and brain of mice, addressing the reduced performance lipid nanoparticles often show when carrying the large messenger RNAs that encode gene editors.

Sep 14Mon
  1. Nature69

    Creating bottom-up RNA transfer vehicles from synthetic protein assemblies.

    AI-designed protein assemblies combined with natural protein domains yielded more than 100 bottom-up RNA transfer vehicles with unique sizes and shapes, surpassing the RNA transfer efficiency of widely used delivery vehicles by several orders of magnitude. Tropism was programmed with computationally designed peptide binders, enabling delivery of therapeutically relevant cargo RNAs across cellular models. One vehicle's in vivo biodistribution was mapped in a mouse at near-single-cell resolution, confirmed as safe, and used for a gene-editing treatment strategy for Duchenne muscular dystrophy in patient-derived cells and a pig.

    Why it matters: Generative AI-designed protein assemblies outperform established RNA delivery vehicles and work in vivo.

  2. Sci Adv47

    Amplification of RNA for identification of Zika and HCV in whole blood.

    A blood drying protocol with thermal treatments and primer-limited reverse transcription stabilizes RNA in whole blood, allowing direct amplification without extraction, purification, or cold-chain logistics. Detection reached 10 copies per microliter for Zika virus and 1 international unit per microliter for HCV, and larger blood volumes achieved single-copy sensitivity without sample loss. Zika and HCV were detected with a portable fluorometer, supporting field-deployable point-of-care diagnostics.

    Why it matters: It removes extraction and cold-chain requirements from whole-blood RNA testing, enabling point-of-care Zika and HCV diagnosis.

Sep 11Fri
  1. Sci Adv56

    Targeting tumor-associated macrophages using mRNA lipid nanoparticles for cytotoxic T lymphocyte-mediated cancer immunotherapy.

    Antibody-coated lipid nanoparticles targeting TREM2 on tumor-associated macrophages delivered mRNA encoding CXCL9 together with a Toll-like receptor agonist, reversing immunosuppression and increasing tumor infiltration and activity of cytotoxic T lymphocytes. Adding PD-L1 and CTLA-4 checkpoint inhibitors produced a CTL-favoring immunological environment and durable memory immunity, supporting TAM reprogramming as a route to better immunotherapy response.

    Why it matters: It offers a targeting solution for mRNA cytokine delivery to macrophages and shows synergy with checkpoint inhibitors.

Sep 7Mon
Sep 1Tue
  1. Cell59

    Viral protease-initiated lytic cell death as a universal antiviral mRNA therapy.

    Gasdermin-D was engineered to carry viral protease-specific cleavage motifs, producing VID activators that trigger lytic cell death only in infected cells. Delivered as LNP-encapsulated mRNA in a hepatitis A virus model, they abolished viral replication and shedding in vivo and eased liver injury via a kill-and-alert mechanism, with activity also shown against Zika virus and SARS-CoV-2. Generative AI-designed cleavage motifs for the SARS-CoV-2 main protease improved antiviral potency.

    Why it matters: It turns viral protease activity into a broadly applicable mRNA kill-and-alert antiviral strategy.

  2. N Engl J Med78

    Eplontersen for Transthyretin Amyloid Cardiomyopathy.

    Eplontersen, an antisense oligonucleotide that reduces hepatic transthyretin production, did not reduce cardiovascular death or recurrent cardiovascular events in transthyretin amyloid cardiomyopathy. In the phase 3 CARDIO-TTRansform trial, 1432 patients received subcutaneous eplontersen 45 mg or placebo every 4 weeks for 140 weeks; the primary composite occurred at a rate ratio of 0.89 (95% CI, 0.73 to 1.09; P = 0.28). The finding leaves no demonstrated outcome benefit for eplontersen on top of standard treatment in ATTR-CM.

    Why it matters: Negative phase 3 result for eplontersen in 1432 patients with ATTR-CM at 140 weeks.

  3. Nat Biotechnol71

    Enhanced antitumor immunity of mRNA vaccines by bioorthogonal-like delayed activation of exogeneous STING.

    Codelivered STING agonists suppress antigen mRNA translation, so the authors engineered Syn-STING, a lipid nanoparticle carrying antigen mRNA, mRNA encoding full-length STING and a DMXAA activator released on a delayed schedule via a biodegradable linker. In humanized STING mouse models with HPV E7 and ovalbumin antigens, the particles localized activation to myeloid antigen-presenting cells, avoided systemic regulatory B cell differentiation and immunocyte apoptosis, suppressed tumor growth and prolonged survival with negligible anti-STING immunity.

    Why it matters: It solves the problem that codelivered STING agonists blunt antigen mRNA translation in mRNA vaccines.

Aug 31Mon
  1. Science66

    Nonviral delivery of chemically modified tRNA rescues nonsense mutations in cystic fibrosis.

    Chemically modified suppressor tRNAs delivered by tailored lipid nanoparticles rescued nonsense mutations in cystic fibrosis. Adding N1-methyladenosine to sup-tRNAs improved premature termination codon readthrough, tRNA aminoacylation, functional persistence, and reduced innate immune activation. The LNP-delivered sup-tRNAs restored CFTR expression and function in bronchial epithelial cells, mouse models, and patient-derived organoids.

    Why it matters: Combines chemical tRNA modification with pulmonary LNP delivery to address the main barriers to sup-tRNA therapy.

  2. JAMA56

    Gene Silencer Therapy in Transthyretin Amyloid Cardiomyopathy: A Meta-Analysis of Outcomes Trials.

    Pooled analysis of the phase 3 trials HELIOS-B and CARDIO-TTRansform (2086 patients with ATTR-CM) found TTR gene-silencing therapy cut the composite of all-cause mortality and recurrent cardiovascular events by 20% (RR, 0.80; 95% CI, 0.69-0.94), reduced all-cause death (HR, 0.74; 95% CI, 0.61-0.91), and preserved 6-minute walk distance (+22.2 m vs placebo). Benefit was significant in patients not on baseline TTR stabilizers (RR, 0.69) but not in those already receiving stabilizer therapy (RR, 0.97). The findings support TTR gene silencing for ATTR-CM and clarify how background stabilizer use shapes the treatment effect.

    Why it matters: It quantifies the overall effect of TTR gene silencers in ATTR-CM and shows benefit depends on baseline stabilizer use.

Aug 27Thu
  1. Sci Adv40

    Surface chemistry governs sex-dependent responses to PEG and zwitterionic siRNA nanocarriers in primary macrophages.

    Surface chemistry drives sex-dependent outcomes of siRNA nanocarriers in primary murine macrophages. Across PEGMMA, CBMA, SBMA and polymeric SBMA pH-responsive nanoparticles, all enabled intracellular siRNA uptake and suppressed TNF-α, but zwitterionic carriers showed sex-specific cytotoxicity and gene knockdown despite similar uptake, while PEGMMA had higher uptake in females with comparable knockdown across sexes. Uptake alone thus fails to predict functional efficacy.

Aug 24Mon
  1. Cell65

    Functional atlas of vertebrate viral RNA elements that stabilize RNA and enhance translation.

    Massively parallel reporter assays covering roughly 200,000 genomic segments from 297 vertebrate-infecting viral genera identified viral RNA elements in 19 genera, grouped into six subclasses, that enhance RNA stability and translation via TENT4-mediated mixed tailing. Diverse TENT4-independent elements also emerged, including Potamipivirus Pt1, which stabilizes linear mRNA to levels comparable to circular RNA by recruiting PAPγ/α for cytoplasmic polyadenylation. The work charts viral RNA regulation and points to elements with RNA therapeutic potential.

    Why it matters: Large-scale virome survey yields catalogued RNA stability elements and a candidate tool for RNA therapeutics.

Aug 19Wed
  1. nature.com71

    Enhanced antitumor immunity of mRNA vaccines by bioorthogonal-like delayed activation of exogeneous STING

    The paper reports a strategy for enhancing the antitumor immunity of mRNA vaccines using bioorthogonal-like delayed activation of exogenous STING. The approach delays STING activation so that it coincides with vaccine-induced antigen expression rather than acting immediately on delivery. No results or quantitative outcomes are stated in the material itself.

    Why it matters: It proposes a timed-activation STING adjuvant strategy for improving mRNA cancer vaccines.

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