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#核酸药物

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Oct 14Wed
  1. biospace.com48

    Alnylam bulls and bears fight it out after business-shaking guidance cut

    Alnylam cut full-year guidance by about $200 million after second-quarter sales of the TTR silencer Amvuttra in transthyretin-mediated amyloidosis fell short, and its stock has dropped from near $500 to around $250. Analysts at Guggenheim question whether the ATTR-CM opportunity is smaller than expected or whether stabilizers from Pfizer and BridgeBio are becoming preferred, while TD Cowen reiterated a $482 target and BMO argues the cut reflects second-line patient exhaustion. Alnylam is running Phase 3 trials of nucresiran in ATTR-CM and ATTR-PN, and a Phase 3 cardiovascular outcomes trial of zilebesiran in hypertension.

  2. 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.

  3. biopharmadive.com64

    Roche extends China deal streak with $1B pact for RNAi obesity drug

    Roche licensed an experimental RNA interference obesity medicine targeting ALK7 from China-based Rona Therapeutics, paying $100 million upfront for full ownership and up to just over $1 billion in milestones plus royalties. The drug joins five other experimental obesity medicines in Roche's pipeline. It is Roche's fifth deal with a China-based drugmaker since the end of August and 10th since the beginning of 2025.

Oct 13Tue
  1. biospace.com65

    Roche expands obesity R&D footprint with Rona deal worth $1B+

    Roche has licensed an RNAi-based ALK7 obesity drug candidate from China's Rona Therapeutics, paying up to $100 million upfront and in near-term milestones plus as much as $1.06 billion in future milestones. ALK7 inhibition may reduce fat deposits while preserving muscle, an option GLP-1 drugs lack. The deal follows Roche returning its anti-myostatin therapy emugrobart to subsidiary Chugai after a mid-stage analysis found it unlikely to produce meaningful weight loss.

  2. 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.

  3. nature.com80

    FDA nod for rare neurology drug

    The FDA has approved Ionis Pharmaceuticals' Zanvastro (zilganersen), the first disease-modifying drug for Alexander disease, a rare progressive and often fatal neurological condition affecting about one person per 1-3 million. The antisense oligonucleotide targets RNA encoding glial fibrillary acidic protein (GFAP), reducing its overproduction in astrocytes, where excess GFAP forms clumps that disrupt myelination. Patients suffer impaired motor function, seizures, intellectual disability and developmental delays.

    Why it matters: First disease-modifying therapy approved for a rare, previously untreatable neurological condition.

Oct 9Fri
  1. biospace.com54

    TRexBio, Retension raise $161.7M in IPOs; City, Iambic set proposed offering terms

    TRexBio raised $116.7 million in its Nasdaq IPO, selling 8.3 million shares at $14 to fund TRB-061, a fusion protein in early-stage development for atopic dermatitis with a Phase 1b topline readout expected mid-2027. Retension Pharmaceuticals raised $45 million at $12 per share to advance RTN-001, a PDE-5 blocker for hypertension, through Phase 2b and into Phase 3. City Therapeutics expects about $158.3 million and Iambic Therapeutics about $135 million from upcoming offerings.

    Why it matters: Four biotech IPOs in one week signal a reopening of the public markets for drug developers.

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.

Oct 2Fri
  1. biospace.com64

    Novartis bets up to $7.8B for an mRNA-encoded T cell engager from China’s Abogen

    Novartis will pay Suzhou-based Abogen Biosciences $575 million upfront, with up to around $7.2 billion in milestones plus royalties, to develop ABO2203, an mRNA-encoded CD3xCD19 T cell engager designed to deplete disease-causing B cells in vivo. First-in-human data in nine relapsed or refractory B cell non-Hodgkin lymphoma patients showed no CRS, dose-limiting toxicities or neurological complications, with 100% objective response at the highest dose. Novartis also gains options to license therapies from Abogen's AI-driven RNA platform; target indications were not disclosed.

Oct 1Thu
  1. Nat Biotechnol50

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

    Screening ionizable lipids with a gene-editor-sized RNA yielded LC-1, a lipid that forms a structure enhancing endosomal escape of large editor mRNAs. Lipid nanoparticles built on LC-1 achieved efficient genome editing in the liver, lung and brain of mice. The work points to cargo size as a design criterion for lipid nanoparticles delivering large gene editors.

    Why it matters: It identifies an ionizable lipid, LC-1, that extends LNP genome editing to liver, lung and brain in mice.

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. biorxiv.org57

    RNA isoform-resolved multiplexed sequencing with bioorthogonal barcoding

    Bobcodes, bioorthogonal barcodes attached at multiple internal positions along cellular RNAs via acylation and click chemistries, enable multiplexed sequencing that preserves splice junction information. Template switching onto tethered bobcodes during cDNA synthesis occurs with greater than 99% accuracy in species mixing experiments, and priming choice selects between 3'-end counting and full-length isoform capture. A BOB-seq v0.1 drug screen detects transcriptome-wide on- and off-target RNA splicing effects and outperforms existing multiplexing RNA sequencing methods in workflow simplicity, sample-to-sample variability, and barcoding accuracy.

    Why it matters: It adds isoform resolution to scalable multiplexed RNA sequencing, enabling transcriptome-wide splicing drug screens.

  4. 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 15Tue
  1. Nat Biotechnol56

    Moderna flu vaccine wins FDA approval.

    The FDA has approved Moderna's mRNA seasonal influenza vaccine mFlusiva for people aged 50-64. It is the first seasonal flu vaccine to use mRNA-based production, encoding full-length hemagglutinin from three WHO-recommended strains in lipid nanoparticles, allowing rapid updates to match circulating strains. In two clinical trials, mFlusiva outperformed GlaxoSmithKline's four-strain vaccine Fluarix in preventing infection or eliciting antibody responses.

    Why it matters: First mRNA-based seasonal flu vaccine approval sets a precedent for rapidly updated influenza vaccines.

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 10Thu
  1. nature.com65

    Moderna flu vaccine wins FDA approval

    The FDA has approved Moderna's mFlusiva, an mRNA-based seasonal flu vaccine, for people aged 50–64. It is the first seasonal influenza vaccine to use mRNA production, encoding full-length hemagglutinin from three WHO-recommended strains delivered in lipid nanoparticles. In two clinical trials, mFlusiva outperformed GlaxoSmithKline's four-strain vaccine Fluarix in preventing influenza infection or eliciting antibody responses.

    Why it matters: First mRNA-based seasonal flu vaccine approval sets a regulatory precedent for Moderna's mRNA platform beyond its earlier vaccines.

Sep 9Wed
  1. nature.com44

    Inhaled siRNA therapy targeting RAGE for pulmonary inflammation: a first-in-human randomized trial

    Inhaled siRNA directed against RAGE was safe and well tolerated in a first-in-human randomized trial, its first test in people after preclinical development. The lung-epithelium-targeted therapy reduced RAGE levels in both serum and bronchoalveolar lavage fluid, supporting gene silencing delivered by inhalation as a route to treating pulmonary inflammation.

    Why it matters: First-in-human evidence that inhaled siRNA can safely silence a pulmonary inflammation target in lung and blood.

Sep 7Mon
Sep 5Sat
  1. Nat Med61

    Inhaled siRNA therapy targeting RAGE for pulmonary inflammation: a first-in-human randomized trial.

    Inhaled ARO-RAGE, a lung-epithelium-targeted siRNA against pulmonary RAGE mRNA, was safe and well tolerated in a first-in-human randomized trial in 58 healthy volunteers and 19 patients with asthma. Plasma levels were low, consistent with drug retention in the lung, and prolonged dose-responsive decreases in serum and bronchoalveolar lavage sRAGE indicated effective pulmonary target engagement. The results support continued clinical development of inhaled therapeutic siRNA for pulmonary inflammation.

    Why it matters: First-in-human data show an inhaled siRNA can safely engage a lung target with minimal systemic exposure.

Sep 2Wed
  1. fiercebiotech.com48

    Is Moderna, Merck's mRNA cancer vaccine win the start of a 'personalized medicine revolution'?

    Merck & Co. and Moderna reported in August that their individualized mRNA cancer vaccine intismeran autogene (V940, mRNA-4157) plus Keytruda significantly improved recurrence-free survival and distant metastasis-free survival versus Keytruda alone in the phase 3 INTerpath-001 trial of 1,137 patients with resected cutaneous melanoma. Detailed data are being held for a future medical meeting, and analysts and academics say the result has revived interest in mRNA-based personalized cancer vaccines. Moderna's stock closed up 177% on the news.

Sep 1Tue
  1. Nat Biotechnol60

    A pervasive RT-qPCR artifact inflates RNA knockdown by RNA-targeting CRISPR.

    Guide RNAs that copurify during RNA extraction inhibit RT-qPCR, causing overestimation of knockdown efficiency for amplicons spanning or upstream of the guide RNA binding site, across all CRISPR systems tested. The artifact is pervasive in how RNA-targeting CRISPR knockdown is routinely quantified. The authors recommend a processive reverse transcriptase with strong strand-displacing activity, plus orthogonal methods, for accurate RT-qPCR measurement.

  2. 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.

  3. 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.

  4. 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 30Sun
  1. nature.com59

    Eplontersen with and without background transthyretin stabilizers in transthyretin amyloid cardiomyopathy: secondary analysis of a phase 3, randomized controlled trial

    A secondary analysis of the CARDIOTTRansform phase 3 randomized controlled trial found that eplontersen, a transthyretin-targeting antisense oligonucleotide, benefited patients with transthyretin amyloid cardiomyopathy who were not on transthyretin stabilizers at baseline, but showed no such effect in those already taking stabilizers. The result separates responders from non-responders by background therapy. Findings were presented at the 2026 ESC Congress.

    Why it matters: It identifies baseline transthyretin stabilizer use as a factor determining which cardiomyopathy patients benefit from eplontersen.

Aug 28Fri
  1. Lancet61

    Safety and lipoprotein(a)-lowering effects of Kylo-11, a non-canonical, long-duration small interfering RNA targeting lipoprotein(a): a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial.

    A single subcutaneous dose of Kylo-11, a very long-acting small interfering RNA targeting lipoprotein(a), cut median serum lipoprotein(a) by up to -97% at 48 weeks in healthy adults with elevated concentrations, with reductions of -53% at 9 mg and -96% in participants above 200 nmol/L given 225 mg. In the 70 dosed participants, adverse events occurred in 53%, mostly grade 1-2 and deemed unrelated; there were no serious or drug-related events. The findings support durable lipoprotein(a) lowering from one dose.

    Why it matters: It shows a single siRNA dose can durably lower lipoprotein(a) for up to 48 weeks in humans.

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 25Tue
  1. Sci Adv54

    RNA delivery to the corneal endothelium using charge-altering releasable transporters.

    A charge-altering releasable transporter (CART) delivers RNA selectively to the corneal endothelium, a non-regenerative cell layer whose dysfunction causes blinding diseases. CART-RNA nanoparticles proved safe in mice, carried diverse RNA cargoes including circular RNA and CRISPR/Cas9, allowed redosing, and achieved corneal gene editing. The platform also transfected human donor corneal endothelial cells in vitro and corneal endothelium in a non-human primate in vivo.

Aug 24Mon
  1. Science61

    De novo design of RNA pseudoknots with deep learning.

    Deep learning tools achieved accurate de novo design of RNA pseudoknot secondary structures, with generative AI matching experienced human designers on most blind challenges in an Eterna competition involving 57 pseudoknots. Designs were evaluated by single nucleotide-resolution chemical mapping, compensatory mutagenesis, and cryo-electron microscopy, and AI-generated molecules with accurate secondary structures formed well-ordered 3D folds stabilized by noncanonical tertiary interactions not modeled during design. Success was guided by an RNet foundation model trained on prior chemical mapping data, indicating that difficult RNA design tasks may be tractable without first solving RNA 3D structure prediction.

    Why it matters: AI matches expert human designers on blind RNA pseudoknot design without requiring 3D structure prediction.

  2. 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 21Fri
  1. biocentury.com56

    Mapping first steps toward scaling genetic medicines: C-Path’s Romero on the BioCentury Show

    The Critical Path Institute's One to Millions Initiative is building a development framework for individualized rare disease therapies, starting with antisense oligonucleotides, and aims to extend it to all genetically defined diseases, including mutation-segmented subtypes of Parkinson's disease. CEO and CSO Klaus Romero said the bottleneck is the absence of a standardized regulatory and development system, and the initiative's first deliverables include a shared safety database meant to reduce repeated preclinical studies. The effort implements FDA's Plausible Mechanism Framework through consortia of companies, academics, patient groups and regulators sharing data.

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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