Zapomeran

ARCT-032 (CF) Phase 2 study enrollment remains on schedule; the decision to proceed into Phase 3 expected Q4 2026 ARCT-810 (OTC Deficiency) Phase 2 study enrollment and dosing completed; data and regulatory plan to be communicated Q3 2026 Arcturus regains global rights to KOSTAIVE® and infectious disease portfolio; receives $12 million in cash and $16 million in released liabilities and R&D credits Investor conference call at 4:30 p.m. ET today SAN DIEGO--(BUSINESS WIRE)--Aug. 6, 2026-- Arcturus Therapeutics Holdings Inc. (the “Company”, “Arcturus”, Nasdaq: ARCT), a messenger RNA medicines company focused on the development of liver and respiratory rare disease therapeutics, today announced its financial results for the quarter ended June 30, 2026, and provided corporate updates. “We are encouraged by the continued progress of our ARCT-032 Phase 2 cystic fibrosis study, with active screening and ongoing enrollment across sites in the United States, Israel, and Turkey. With dosing completed of all subjects in our ARCT-810 Phase 2 OTC deficiency study, we look forward to sharing the data and regulatory plan later this quarter,” said Joseph Payne, President & CEO of Arcturus. “We are also pleased to regain strategic control of KOSTAIVE® and our infectious disease vaccine portfolio, enhancing our ability to increase the value of our validated sa-mRNA vaccine platform.” Recent Corporate Highlights ARCT-032, an inhaled mRNA therapeutic candidate for cystic fibrosis, continues to advance in an open-label Phase 2 study in people with Class I CF mutations. Cohort 4 is evaluating 10 mg daily dosing, via inhalation, over 12 weeks and monitoring safety and evidence of early clinical benefit, including pulmonary function measures such as ppFEV1 and lung clearance index (LCI), quality-of-life measures, and high-resolution computed tomography (HRCT) imaging. Enrollment is advancing as expected, with active screening and enrollment in the U.S., Israel, and Turkey. Israel and Turkey are geographies with a high prevalence of individuals with Class I/null CF mutations, supporting recruitment efforts in the ongoing study. The decision to advance ARCT-032 into Phase 3 is expected in Q4 2026, triggering significant resources and support from Thermo Fisher. Arcturus announced a strategic collaboration with Thermo Fisher Scientific to advance ARCT-032 for cystic fibrosis. Thermo Fisher will provide Phase 3 manufacturing, clinical research, and related services. If Phase 2 yields positive results, Arcturus expects to conduct its Phase 3 program through Thermo Fisher’s PPD™ clinical research business. Subject to regulatory approval of ARCT-032, Thermo Fisher will receive exclusive commercial manufacturing rights under a separate commercial agreement. ARCT-810, an mRNA therapeutic candidate for OTC deficiency, has completed enrollment of the ongoing Phase 2 study, and all enrolled subjects have completed study drug dosing. The Company continues to evaluate supplementary data to inform regulatory discussions and preparation for an End-of-Phase 2 meeting regarding the path forward across adult and pediatric development. Data and the regulatory plan for this program is expected to be communicated later this quarter. Arcturus and CSL Seqirus have concluded their sa-mRNA collaboration through a termination and settlement agreement following a joint review of the partnership. Under the agreement, Arcturus regained global rights to KOSTAIVE® and the broader infectious disease vaccine portfolio, including seasonal influenza, pandemic influenza, RSV, and EBV vaccine programs, subject to existing arrangements with Meiji Seika Pharma for the 2026-2027 season in Japan. The agreement also resolves the arbitration relating to a European regulatory approval milestone payment. Under the agreement, CSL Seqirus will make a one-time cash payment of $12 million to Arcturus. In addition, Arcturus will be released from liabilities associated with an R&D credit with an aggregate value of approximately $16 million. With strategic control of the portfolio returned to Arcturus, the Company intends to evaluate opportunities to maximize its future value, including development, commercialization, and partnering opportunities related to KOSTAIVE®, and the broader infectious disease vaccine portfolio. Under the agreement, CSL Seqirus will make a one-time cash payment of $12 million to Arcturus. In addition, Arcturus will be released from liabilities associated with an R&D credit with an aggregate value of approximately $16 million. With strategic control of the portfolio returned to Arcturus, the Company intends to evaluate opportunities to maximize its future value, including development, commercialization, and partnering opportunities related to KOSTAIVE®, and the broader infectious disease vaccine portfolio. “We remain focused on disciplined execution and capital allocation as we advance our rare disease programs,” said Dennis Mulroy, Chief Financial Officer of Arcturus. “The CSL Seqirus termination and settlement agreement strengthens our financial position, and the Thermo Fisher collaboration supports execution of late-stage development for our CF program. We continue to maintain a strong balance sheet and cash runway of over two and a half years through year end 2028, allowing our company to reach important clinical and regulatory milestones for its rare disease pipeline.” Financial Results for the three months ended June 30, 2026 Cash Position and Balance Sheet Cash and cash equivalents were $191.5 million as of June 30, 2026, and $230.9 million on December 31, 2025, for a decrease of $39.4 million. The decrease was primarily driven by cash used related to ongoing clinical development activities, including the continued advancement of the Company's ARCT-032 cystic fibrosis and ARCT-810 OTC deficiency programs. Revenue in conjunction with strategic alliances and collaborations Revenue was $3.0 million and $5.0 million for the three and six months ended June 30, 2026, respectively, compared with $28.3 million and $57.7 million in the comparable periods last year. The decreases in revenue were primarily attributable to lower revenue recognized under the CSL Seqirus collaboration as the Company progressed toward the termination of the agreement and regaining rights to KOSTAIVE® and its broader infectious disease vaccine portfolio. Research and development expenses Research and development expenses were $17.5 million and $39.0 million for the three and six months ended June 30, 2026, respectively, compared with $29.6 million and $64.5 million for the corresponding periods in 2025. The decreases were primarily driven by lower research and development spending including reduced salaries, wages, benefits and facilities costs as the Company continued to advance its highest-priority programs while maintaining a disciplined approach to capital allocation. General and administrative expenses General and administrative expenses were $11.0 million and $20.5 million for the three and six months ended June 30, 2026, respectively, compared with $10.3 million and $21.7 million in the comparable periods last year. Overall, general and administrative expenses remained relatively consistent across periods with a slight quarter-to-date increase due to legal fees partly offset by reduced salaries, wages, benefits and facilities costs. Net loss Net loss was $23.8 million and $50.7 million for the three and six months ended June 30, 2026, or a net loss per share of $0.84 and $1.79, compared to a net loss of $9.2 million and $23.3 million for the three and six months ended June 30, 2025, or a net loss per share of $0.34 and $0.86. Earnings Call: Thursday, August 6, 2026 @ 4:30 p.m. ET Domestic: 1-800-347-6865 International: 1-203-518-9757 Conference ID: ARCTURUS Webcast: Link About Arcturus Founded in 2013 and based in San Diego, California, Arcturus Therapeutics Holdings Inc. (Nasdaq: ARCT) is a messenger RNA medicines company focused on the development of liver and respiratory rare disease therapeutics with enabling technologies: (i) LUNAR® lipid-mediated delivery, (ii) STARR® mRNA technology (sa-mRNA) and (iii) mRNA drug substance along with drug product manufacturing expertise. Arcturus developed KOSTAIVE®, the first self-amplifying messenger RNA (sa-mRNA) COVID vaccine in the world to be approved. Arcturus' strategic collaborations include Thermo Fisher Scientific for ARCT-032 manufacturing and development, BARDA for pandemic influenza initiatives, and ARCALIS, a Japanese joint venture focused on manufacturing mRNA vaccines and therapeutics. Arcturus’ pipeline includes RNA therapeutic candidates to potentially treat cystic fibrosis (CF) and ornithine transcarbamylase (OTC) deficiency. Arcturus’ versatile RNA therapeutics platforms can be applied toward multiple types of nucleic acid medicines including messenger RNA, small interfering RNA (siRNA), circular RNA, antisense RNA, self-amplifying RNA, DNA, and gene editing therapeutics. Arcturus' technologies are covered by its extensive patent portfolio (over 500 patents and patent applications in the U.S., Europe, Japan, China, and other countries). For more information, visit www.ArcturusRx.com. Please connect with us on X and LinkedIn. Forward-Looking Statements This press release contains forward-looking statements that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. Any statements, other than statements of historical fact included in this press release, are forward-looking statements, including those regarding strategy, future operations, the likelihood of success of the Company’s pipeline (including ARCT-032 and ARCT-810), the likelihood that the Company will continue to advance its rare disease therapeutics portfolio including its inhaled mRNA therapy, the likelihood that the ARCT-032 (CF) Phase 2 study enrollment will remain on schedule, the timing for a decision to proceed into a Phase 3 study for ARCT-032, the communication of a data and regulatory plan for ARCT-810 and timing thereof, the likelihood that the Company will be able to increase the value of its sa-mRNA vaccine platform including likelihood that the Company will develop, commercialize or seek partnership opportunities related to KOSTAIVE and its other infectious disease vaccine programs, the ability of the Company to reach important clinical and regulatory milestones for its rare disease pipeline, the likelihood that clinical data, including interim data, will be predictive of future clinical results, its current cash position and expected cash burn and runway, and the impact of general business and economic conditions. Arcturus may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in any forward-looking statements such as the foregoing and you should not place undue reliance on such forward-looking statements. These statements are only current predictions or expectations, and are subject to known and unknown risks, uncertainties, and other factors that may cause our or our industry’s actual results, levels of activity, performance or achievements to be materially different from those anticipated by the forward-looking statements, including those discussed under the heading "Risk Factors" in Arcturus’ most recent Annual Report on Form 10-K, and in subsequent filings with, or submissions to, the SEC, which are available on the SEC’s website at www.sec.gov. Except as otherwise required by law, Arcturus disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date they were made, whether as a result of new information, future events or circumstances or otherwise. ARCTURUS THERAPEUTICS HOLDINGS INC. AND ITS SUBSIDIARIES CONDENSED CONSOLIDATED BALANCE SHEETS June 30, 2026 December 31, 2025 (in thousands, except par value information) (unaudited) Assets Current assets: Cash and cash equivalents $ 191,483 $ 230,909 Accounts receivable 1,813 5,564 Prepaid expenses and other current assets 3,865 4,973 Total current assets 197,161 241,446 Property and equipment, net 5,363 6,736 Operating lease right-of-use assets, net 19,758 21,081 Non-current restricted cash 2,028 1,885 Total assets $ 224,310 $ 271,148 Liabilities and stockholders’ equity Current liabilities: Accounts payable $ 4,414 $ 4,235 Accrued liabilities 22,846 23,898 Deferred revenue 6,276 8,246 Total current liabilities 33,536 36,379 Operating lease liabilities, net of current portion 18,966 20,784 Total liabilities 52,502 57,163 Stockholders’ equity Common stock, $0.001 par value; 60,000 shares authorized; issued and outstanding shares were 28,423 at June 30, 2026 and 28,414 at December 31, 2025 28 28 Additional paid-in capital 737,119 728,547 Accumulated deficit (565,339 ) (514,590 ) Total stockholders’ equity 171,808 213,985 Total liabilities and stockholders’ equity $ 224,310 $ 271,148 ARCTURUS THERAPEUTICS HOLDINGS INC. AND ITS SUBSIDIARIES CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS (unaudited) Three Months Ended Six Months Ended June 30, June 30, (in thousands, except per share data) 2026 2025 2026 2025 Revenue: Collaboration revenue $ 880 $ 24,510 $ 1,490 $ 49,987 Grant revenue 2,079 3,791 3,530 7,696 Total revenue 2,959 28,301 5,020 57,683 Operating expenses: Research and development, net 17,515 29,579 39,042 64,471 General and administrative 10,989 10,338 20,454 21,654 Total operating expenses 28,504 39,917 59,496 86,125 Loss from operations (25,545 ) (11,616 ) (54,476 ) (28,442 ) Finance income, net 1,819 2,567 3,751 5,339 Other expense (59 ) (127 ) (24 ) (149 ) Net loss before income taxes (23,785 ) (9,176 ) (50,749 ) (23,252 ) Provision for income taxes — 4 — 4 Net loss $ (23,785 ) $ (9,180 ) $ (50,749 ) $ (23,256 ) Net loss per share, basic and diluted $ (0.84 ) $ (0.34 ) $ (1.79 ) $ (0.86 ) Weighted-average shares outstanding, basic and diluted 28,423 27,129 28,422 27,118 Comprehensive loss: Net loss $ (23,785 ) $ (9,180 ) $ (50,749 ) $ (23,256 ) Comprehensive loss $ (23,785 ) $ (9,180 ) $ (50,749 ) $ (23,256 ) View source version on businesswire.com: https://www.businesswire.com/news/home/20260806642697/en/ Arcturus Therapeutics Public Relations & Investor Relations Neda Safarzadeh VP, Head of IR/PR/Marketing (858) 900-2682 IR@ArcturusRx.com Source: Arcturus Therapeutics Holdings Inc.

📌 NATURE REVIEWS DRUG DISCOVERY · 2026 综述 迈向 mRNA 治疗 2.0：从疫苗到治愈一切 从 COVID-19 疫苗到基因组编辑与体内 CAR-T——一次看懂 mRNA 疗法的前世 · 瓶颈 · 未来 👨🔬 Kenneth R. Chien · Kylie S. Foo · Nevin Witman（Karolinska Institutet）DOI: 10.1038/s41573-026-01459-7 ▎文章摘要mRNA 技术不仅催生了对抗传染病的疫苗，也正成为治疗罕见病与常见病的下一代药物基础。十年临床试验揭开了 mRNA 药物的关键障碍，而跨学科技术创新正逐一突破——某些进展甚至把基因治疗、细胞治疗和 mRNA 治疗融合在了一起。 本综述系统梳理了 mRNA 治疗在罕见病酶替代、个性化癌症免疫、基因组修饰、免疫细胞重编程四大领域的进展。真正的胜负手是：临床可行的体内递送系统、真正"免疫沉默"的可重复给药配方、以及摆脱肝脏依赖的器官靶向递送。 📑 本文你将读到01 引言：iPhone 1.0 与 mRNA 2.0 的隐喻02 mRNA 1.0 简史：Karikó 改写游戏规则03 从疫苗到治疗：五大核心挑战04 分泌蛋白疗法：VEGFA 与心衰治疗05 mRNA 编码抗体：双特异性时代06 罕见病酶替代：mRNA 替代 AAV？07 个性化癌症免疫：5 年降 49% 复发08 mRNA 基因组编辑：体内 CRISPR09 免疫细胞重编程：体内 CAR-T10 迈向 mRNA 2.0+：下一程的胜负手 01｜引言：iPhone 1.0 与 mRNA 2.0 的隐喻 "We're here to put a dent in the universe. Otherwise, why else even be here?"—— 史蒂夫·乔布斯，1985 作者用乔布斯这句名言开篇，把 mRNA 治疗比作"生命界的 iPhone"——一款被寄予厚望的颠覆性平台。 iPhone 从 1.0 进化到 17.0，依赖触摸屏、芯片、摄像头、电池、App 生态的迭代；mRNA 想从 1.0（疫苗）走向 2.0（治愈一切），也需要类似的组件级突破。而 COVID-19 疫苗的成功，已把 mRNA 推到了"普及"级别。 但 mRNA 治疗的真正"划痕"还没有留下——它现在还抢不走重组蛋白、抗体、siRNA、AAV 基因治疗和细胞治疗的市场。要打破僵局，需要一系列技术整合： 5mRNA 核心组件可优化 6+已进入临床的治疗方向 20+临床管线候选分子 02｜mRNA 1.0 简史：Karikó 改写游戏规则 2023 年诺贝尔生理学或医学奖授予 Karikó 与 Weissman，表彰他们发现：化学修饰 mRNA 可以躲避天然免疫系统的攻击——这是 mRNA 1.0 的起点。未修饰的 mRNA 一旦被细胞识别，就会被当成"病毒入侵"，蛋白根本来不及翻译就被降解。 为什么 mRNA 治疗要花 30 年才走到临床？因为未修饰的 mRNA 既是"危险的病原体"，又非常"短命"。要在体内既躲避免疫、又稳定表达、还高效递送，需要从五个维度同时优化一个分子。 🧬 一个 mRNA 分子的五件"外衣" 5′ 帽（cap）｜7-甲基鸟苷，新一代共转录加帽效率 ~95%，是三大获批疫苗的标配 5′ UTR｜翻译启动的"开关"，AI 正在改写它的设计规则（UTRGAN、LinearDesign2） 编码区（ORF）｜密码子优化 + N1-甲基假尿苷，蛋白表达可提升 40 倍以上 3′ UTR｜决定 mRNA 半衰期，支持 AI 引导设计与细胞类型筛选 poly(A) 尾｜与 5′ 帽形成"闭环"保护 mRNA，多尾结构可让蛋白产量提升 20 倍、持续 14 天 图 1｜mRNA 治疗的双引擎：LNP 递送系统（四种脂质）与 mRNA 分子结构（五组件）。 🚚 LNP 的"快递四件套"：可离子化阳离子脂（装载 mRNA + 内体逃逸，临床用 SM102 / ALC0315 / LP-01 / MC-3）、PEG 脂（稳定）、磷脂（膜结构）、胆固醇（膜稳定）。这就是 mRNA 1.0 的核心配方。 ⏳ Box 1｜三种"长寿 mRNA"circRNA（环状）：闭环抗外切酶，半衰期更长；RXRG001 已进 Phase I/II 治疗放疗口干症saRNA（自扩增）：编码 nsP1-4 复制酶自我复制，代表产品 Kostaive 疫苗多尾 poly(A)：小鼠中 mRNA 水平 +20 倍，蛋白持续 14 天 🤖 Box 2｜AI 工具箱BiLSTM-CRF（密码子优化）· GEMORNA（生成式 mRNA 设计）· LinearDesign2（UTR+编码区协同）· AGILE（AI 设计 LNP） 03｜从疫苗到治疗：五大核心挑战 把 mRNA 从疫苗迁移到治疗，不只是"换一种蛋白"。作者总结了七类核心挑战（Table 1），既是机会也是枷锁： 免疫沉默 LNP所有非疫苗应用必需 → LNP 工程化 细胞类型限制性表达仅肝细胞/造血干细胞（体外）实现 → 配体偶联 LNP、miRNA 开关 肝外递送心/肾/肌肉等均在临床前 → SORT 脂质、雾化吸入 延长蛋白表达酶替代治疗刚需 → circRNA、saRNA、多 poly(A) mRNA 纯度 & 高体内效率超纯化去双链杂质；AI 优化帽-尾工程 生产速度个性化癌症疫苗的命脉 → 加速 DNA 模板构建 04｜分泌蛋白疗法：VEGFA 与心衰治疗 mRNA 治疗大规模走出疫苗的"人源第一针"，其实发生在治疗心血管疾病的战场上——主角是 VEGFA（血管内皮生长因子 A），刺激血管新生的明星分子。 它的临床故事有三个独特之处：首批非疫苗 mRNA 临床试验、首个"裸露 mRNA"（无 LNP）给药系统、心脏内注射 Phase II 概念验证。 图 2｜分泌蛋白疗法开山之作：皮下/心内注射裸 VEGFA mRNA → 局部蛋白分泌 → 血管新生；右图为注射后 VEGF 浓度与皮肤血流改善曲线（剂量依赖）。 💡 三个关键启示 ① 裸 mRNA 也能被细胞摄取，心肌细胞直接吸收，规避 LNP 免疫原性； ② 疗效未必需要感染每个细胞——VEGFA 是旁分泌因子，局部少量表达就足够； ③ 心脏内注射范围有限，远处心肌几乎不表达——成为肝外递送研究的强动机。 另一尝试：IL-2 与自身免疫病Moderna 的 mRNA-6231 将 IL-2 突变体与 HSA 融合以延长半衰期，选择性激活 Treg 细胞。可惜开发已停止，临床数据未公开。 05｜mRNA 编码抗体：双特异性时代 抗体药统治着现代生物医药——但 mRNA 给了它们一个全新可能：让患者自己的肝脏成为"抗体工厂"。 🧬 BNT142（BioNTech）：编码 CLDN6 × CD3 双特异性抗体。静脉注射后肝脏摄取 LNP–mRNA 并将抗体分泌入血，24–72 小时达峰。对卵巢癌等对免疫检查点抑制剂不敏感的实体瘤，Phase I/II 已见初步疗效。 🦟 mRNA-1944（Moderna）：把抗基孔肯雅病毒（CHIKV）的中和抗体全序列塞进 mRNA。所有受试者均产生预测保护水平的中和抗体；但 NHP 到人体翻译严重偏低，最终未进 Phase II。 意义｜mRNA 抗体理论上 4–6 周完成"序列→GMP 制剂"，是应急制造与大流行响应的理想平台。 06｜罕见病酶替代：mRNA 替代 AAV？ 过去的二十年，酶替代疗法为众多罕见病打开了第一道门——但重组蛋白半衰期短、AAV 有免疫排斥和载荷限制。mRNA 提供了第三条路。 🥼 丙酸血症（mRNA-3927）：由 PCCA/PCCB 基因突变导致的罕见遗传代谢病。Moderna 的 mRNA-3927 同时编码 PCC 酶的 α（PCCA）和 β（PCCB）两个亚基——一次给药、两种蛋白、定向运输到线粒体。 图 3｜mRNA 酶替代疗法：LNP 同时递送 PCCA+PCCB mRNA → 蛋白进入线粒体 → 装配 PCC 全酶 → 丙酰-CoA 转化。Interim 分析：16 名患者中 8 人 MDE 风险降低 70%。 甲基丙二酸血症（mRNA-3705）｜线粒体靶向序列加入 UTR，APCs 表达降低；两项临床进行中 糖原贮积病 1a（mRNA-3745）｜2025 年 11 月项目中止（管线重排） OTC 缺乏症（ARCT-810）｜Phase II 进行中 囊性纤维化（ARCT-032 / VX-522）｜吸入递送；VX-522 因耐受性问题 2026 年 5 月终止 更精彩的是 BEAM-301｜不用表达蛋白，直接用 mRNA 编码的腺嘌呤碱基编辑器修复 G6Pase 的 R83C 突变，小鼠中可修复 60% 致病等位基因、恢复血糖稳态。 07｜个性化癌症免疫：5 年降 49% 复发 如果说 mRNA 治疗有一颗"皇冠上的明珠"，那一定是个性化癌症疫苗——每位患者肿瘤突变都不一样，理论上只有 mRNA 平台能在数周内为单个患者量身定制多抗原疫苗。 🧬 mRNA-4157（intismeran autogene）：2026 年 1 月公布，高风险切除黑色素瘤患者接受 mRNA-4157 + pembrolizumab（PD-1 抑制剂）联合治疗，5 年随访复发风险降低 49%——mRNA 治疗在实体瘤领域最硬核的证据之一。 图 4｜个性化癌症免疫疗法闭环：肿瘤活检 → 测序 → 识别新抗原 → 生成 DNA 模板 → 体外转录 → LNP → 皮下注射 → 激活 APCs → T 细胞免疫。 🧪 autogene cevumeran（BioNTech/Genentech）：胰腺癌（PDAC）以"突变少、免疫冷"著称，被视为 mRNA 疫苗"死穴"。但 16 人 I 期显示：联合 atezolizumab + 化疗后，8 名应答者 3 年复发风险显著降低，部分患者体内可检测到持续 4 年的肿瘤特异性 T 细胞。 "现成疫苗"路径｜BNT116 针对 NSCLC 6 个共享抗原，探索"开箱即用"替代个性化策略，加快临床普及。 08｜mRNA 基因组编辑：体内 CRISPR mRNA 治疗在基因组编辑领域找到了最契合的语境——基因编辑的"一次性"特征刚好抵消 mRNA 表达短暂的短板。 🔪 NTLA-2001（Intellia/Regeneron）：首个进入临床的 mRNA 基因编辑疗法，靶向肝脏 TTR 基因治疗转甲状腺素淀粉样变（ATTR）。Phase I 单次用药后血清 TTR 蛋白平均下降 87%，2024 年进入 Phase III。 图 5｜mRNA 基因组编辑双管齐下：a 基因敲除（NTLA-2001：Cas9 mRNA + sgRNA → 核内 indel → 敲除 TTR）；b 碱基编辑（VERVE-102：Cas9–脱氨酶 → 不切 DNA 精确改碱基 → 关闭 PCSK9）。 💉 VERVE-102（Verve/Eli Lilly）：搭载新型 GalNAc 修饰 LNP，更精准靶向肝细胞，关闭 PCSK9 基因降低 LDL-C（早期数据 20–70%）。上一代 VERVE-101 曾因一例肝酶升高+血小板减少暂停，VERVE-102 已获 FDA 快速通道。 👶 世界首例 N-of-1 基因编辑（CPS1 缺乏症）出生即全基因组测序识别 Q335X 突变 → 6 个月设计+制备 → FDA 6 个月内批准 → 7、8 月龄两次静脉注射 → 血氨下降、蛋白耐受改善、无重大不良反应。这是 mRNA + CRISPR 兑现"个体化药物"承诺的标志事件。 🧬 R2 逆转录转座子：基因"插入"新工具——把整段基因插入基因组"安全港"（核糖体 RNA 基因位点）。系统仅两个组分：编码 R2 蛋白（核酸内切酶+逆转录酶）的 mRNA + 模板 RNA，无需 AAV、无需病毒。 图 6｜R2 逆转录转座子：R2 蛋白识别 rDNA 序列 → 切割 → 以模板 RNA 逆转录插入安全港。全 RNA 配方、位点特异性、无病毒载体。 09｜免疫细胞重编程：体内 CAR-T CAR-T 是过去十年最火的细胞疗法，但其制备复杂、价格昂贵、需要预处理化疗——这些都是 mRNA 的"潜在颠覆点"。 🧪 Descartes-08（Cartesian）：用 mRNA 电穿孔体外制备 BCMA 靶向 CAR-T，治疗重症肌无力。Phase IIb 中 83% 患者 12 个月持续应答，无需清淋预处理、无插入突变风险、细胞因子风暴风险低。Phase III AURORA 已启动。 🎯 体内 CAR-T：不用体外制备，直接在患者体内生成 CAR-T——这是 mRNA 治疗的"圣杯"之一。 图 7｜体内生成 CAR-T：CD5 抗体偶联 LNP 装载 FAPCAR mRNA → 选择性结合 CD5+ T 细胞 → 体内重编程 → 靶向 FAP+ 成纤维细胞 → 减少心肌纤维化。Capstan/宾大/NIH 在 NHP 中已获概念验证。 🚀 体内 CAR-T 的革命性意义省去数百万美元/患者的体外制造与扩增 · 省去清淋预处理 · 让 CAR-T 走进自身免疫病与心血管病 · mRNA 瞬时表达降低脱靶毒性 10｜迈向 mRNA 2.0+：下一程的胜负手 作者抛出三个核心问题：mRNA 能否像改变疫苗一样重塑基因组医学？能否用体内重编程把 CAR-T 扩展到实体瘤与自身免疫病？能否进入心脏、肾脏等常见病？ 🎯 1. 肝外递送｜SORT 脂质（肝→脾→肺切换）、吸入式 LNP（肺）、口服 RNACap（肠）、骨髓/HSC 靶向纳米条码筛选 🎯 2. 免疫沉默 LNP｜系统优化可离子化脂质头部基团/linker/侧链、PEG、胆固醇；配合超纯化去除双链 RNA，让 mRNA 可重复给药 🎯 3. "按需挑挑拣拣"工具箱｜酶替代要长表达+可重复给药（circRNA+沉默 LNP）；基因编辑要短但集中（线性 mRNA+肝靶 LNP）；癌症疫苗要速度+多抗原 "Perhaps mRNA 2.0 will be ushered in by technology that enables its efficient delivery to specific cellular locations."—— Towards mRNA Therapeutics 2.0, Nat Rev Drug Discov 2026 📌 一句话总结 mRNA 治疗正从"疫苗即巅峰"走向治愈一切。从分泌蛋白到抗体、从酶替代到基因编辑、从个性化癌症疫苗到体内 CAR-T，六大治疗方向在 2026 年同步进入临床。 真正决定 mRNA 2.0 命运的，是肝外递送 + 免疫沉默 LNP + AI 辅助设计三大技术整合——基础设施比"大陆"本身更重要。 主要参考：Chien KR, Foo KS, Witman N. Towards mRNA therapeutics 2.0. Nature Reviews Drug Discovery, 2026. DOI: 10.1038/s41573-026-01459-7本文为深度解读，学术观点与图片版权归原作者所有。