mRNA肿瘤治疗性疫苗被视为肿瘤免疫治疗领域的重大突破和极具潜力的创新疗法，EVM14基于云顶 新耀自主知识产权的mRNA技术平台研发，是一款靶向5个肿瘤相关抗原（TAA）的通用现货型肿瘤治 疗性疫苗，拟用于治疗多种鳞状细胞癌，包括非小细胞肺鳞癌（sq-NSCLC）和头颈部鳞状细胞癌 （HNSCC）。 EVM14的国际开发已进入新阶段，其新药临床试验申请（IND）此前也已获得中国国家药品监督管理局 （NMPA）的批准，成为云顶新耀首个实现中美IND"双获批"的mRNA肿瘤治疗性疫苗。在EVM14 I期 临床试验探索的瘤种中，大多数患者会表达5个TAA之一。其中，约96%的非小细胞肺鳞癌（sq- NSCLC）患者和97%的头颈部鳞状细胞癌（HNSCC）患者检测到至少一个TAA基因的表达。 "当前，全球鳞癌患者群体庞大，现有免疫疗法和靶向疗法难以形成持久的免疫记忆，仍存在巨大的未 满足医疗需求。肿瘤相关抗原疫苗EVM14能够作为现有疗法的有力补充，并可能减少复发，有望帮助 患者实现'长期无癌生存'的获益。"云顶新耀首席执行官罗永庆表示。 从临床设计来看，EVM14的I期临床试验设计包含EVM14单药队列和EVM1 ...

Core Insights - Arcturus Therapeutics Holdings Inc. reported interim results from its Phase 2 trial of ARCT-032, an inhaled mRNA therapy for cystic fibrosis, leading to a decline in stock price by 56.30% to $10.12 [8] Group 1: Trial Results - The second cohort of the Phase 2 trial involved six Class I CF adults receiving daily doses of 10 mg ARCT-032 for 28 days, with the treatment being generally safe and well-tolerated [1] - Initial analysis of FEV₁ values from Day 1 to Day 28 did not show meaningful improvement [4] - A post hoc exploratory analysis indicated improvements in lung function for four out of six participants, with an average absolute increase of 3.8% and a relative increase of 5.1% in percent predicted FEV₁ (ppFEV₁) [5] Group 2: Safety and Efficacy - Treatment-related adverse events (AEs) were observed in the Phase 1 study but ceased with continued dosing, and a serious adverse event (SAE) was not deemed related to ARCT-032 [2] - High-resolution computed tomography (HRCT) scans showed reductions in mucus burden in four Class I CF participants, indicating therapeutic activity of ARCT-032 [6] - The ongoing third cohort aims to assess dose escalation at 15 mg and further evaluate safety and tolerability [3] Group 3: Future Directions - Data from the second cohort and ongoing third cohort will inform future studies, including a planned 12-week safety and preliminary efficacy trial set to begin in the first half of 2026 [7] - Analysts suggest that the efficacy of ARCT-032 may improve with longer treatment duration or higher doses, aiming to reduce data variability [8]

Core Viewpoint - The study highlights the critical role of Anxa1 protein in the efferocytosis of macrophages during acute pancreatitis and presents a novel mRNA therapy using nanoliposomes to alleviate the condition by suppressing the STING pathway and promoting efferocytosis [2][8]. Group 1: Acute Pancreatitis Mechanism - Acute pancreatitis (AP) is characterized by necrotic cell death of acinar cells, leading to pancreatic necrosis and the release of damage-associated molecular patterns, pro-inflammatory mediators, and chemokines [5]. - During the acute phase of AP, macrophages rapidly clear apoptotic cells through a process known as efferocytosis, which prevents inappropriate inflammatory responses [5]. - Anxa1 protein plays a significant role in efferocytosis by binding to phosphatidylserine on the surface of apoptotic cells in a calcium-dependent manner, facilitating macrophage phagocytosis [5][6]. Group 2: mRNA Therapy Development - Recent years have seen mRNA-based therapies emerge as a treatment strategy, but their clinical application has been limited due to poor mRNA stability [5]. - Researchers have utilized nanocarriers to enhance the stability and targeting capability of mRNA, with nanoliposomes being used for the delivery of siRNA and mRNA [5]. - The study confirms that the absence of Anxa1 protein eliminates the efferocytosis of pancreatic macrophages, leading to the accumulation and necrosis of apoptotic acinar cells [6]. Group 3: Research Findings - The research team demonstrated that Anxa1 mRNA-loaded nanoliposomes can restore macrophage efferocytosis by inhibiting the cGAMP-cGAS-STING pathway, thereby alleviating the pathological condition of acute pancreatitis [6]. - This study reveals the potential therapeutic value of Anxa1 in the context of acute pancreatitis and showcases a novel nanotechnology approach for treatment [8].

Core Viewpoint - The research identifies a novel ionizable lipid, C-a16, which reduces immunogenicity and enhances mRNA delivery efficiency, providing a promising avenue for mRNA therapies and vaccines [3][5][8]. Group 1: Research Findings - The study published in Nature Biomedical Engineering highlights the development of C-a16, an antioxidant ionizable lipid that shows significantly reduced immunogenicity [3][5]. - C-a16, when incorporated into lipid nanoparticles (LNP) for mRNA delivery, decreases the generation of reactive oxygen species (ROS), thereby prolonging protein expression duration [7][8]. - In vivo experiments demonstrated that C-a16-LNP significantly improved gene editing efficiency by 2.8 times and increased protein expression levels by 3.6 times compared to commercial LNPs [7]. Group 2: Implications for mRNA Therapy - The findings suggest that C-a16 could enhance the therapeutic applications of mRNA by inducing stronger antigen-specific immune responses when delivering mRNA encoding tumor neoantigens or SARS-CoV-2 spike protein [7][8]. - The research indicates a potential shift in mRNA delivery systems, focusing on reducing immunogenicity while improving efficacy, which is crucial for the success of mRNA-based therapies and vaccines [3][8].

Core Viewpoint - The article discusses the advancements in mRNA therapies, particularly focusing on the development of non-inflammatory lipid nanoparticles (NIF-LNP) to enhance the delivery and efficacy of mRNA treatments for chronic lung injuries [1][2][9]. Group 1: mRNA Therapy and Challenges - mRNA therapies have revolutionized the treatment of various diseases, but the use of lipid nanoparticles (LNP) is limited due to systemic inflammatory responses and side effects [1][5]. - Therapeutic mRNA requires significantly higher protein levels (up to 1000 times) compared to preventive mRNA vaccines, which may lead to increased reactogenicity and reduced transfection efficiency [1]. Group 2: Research Development - A study published in Nature Communications introduced a novel non-inflammatory lipid nanoparticle (NIF-LNP) that activates V-ATPase to enhance RNA nanotherapeutics for chronic lung injury [2][3]. - The NIF-LNP formulation, incorporating ursolic acid, demonstrated a 40-fold increase in protein expression in the lungs compared to traditional LNPs without significant reactogenicity [5]. Group 3: Mechanism and Clinical Application - The study revealed that ursolic acid activates the V-ATPase complex, promoting endosomal acidification and enhancing mRNA cytoplasmic release while maintaining endosomal stability [6]. - A lyophilized formulation of NIF-LNP was developed, showing good aerosolization and stability for over 90 days, with effective mRNA transfection in preclinical models [7].

Core Viewpoint - The company, Ginkgo Bioworks, is balancing operational sustainability with future growth through a dual strategy of "licensing in + independent research and development" to drive innovation and revenue generation [1][2]. Group 1: Business Strategy - Ginkgo Bioworks has achieved stable cash flow through the introduction of large commercial products while focusing on cutting-edge mRNA therapies, resulting in the development of key products such as EVM14, EVM16, and CAR-T [1][3]. - The company has established a comprehensive technology platform that includes antigen design, mRNA sequence optimization, lipid nanoparticle delivery technology, and industrial production capabilities, making it one of the few companies with end-to-end capabilities in the industry [3][6]. Group 2: Financial Performance - Financial data indicates that Ginkgo Bioworks expects to generate revenue of 707 million yuan in 2024, representing a year-on-year increase of 461%, driven by three commercialized products [3]. - The company aims to achieve sales of 10 billion yuan by 2030, leveraging its existing product portfolio [3]. Group 3: Competitive Advantage - Ginkgo Bioworks possesses a proprietary lipid library of over 500 types, which supports various projects including vaccines and CAR-T therapies [5][6]. - The company has developed an AI algorithm for efficient antigen sequence design, with its algorithm system now in its third generation, and has established a lipid nanoparticle delivery technology platform with patent protections [6]. Group 4: Market Position - Major pharmaceutical companies like AbbVie, Eli Lilly, Johnson & Johnson, and AstraZeneca are investing in mRNA therapies and CAR-T technologies, indicating a competitive landscape [4]. - Ginkgo Bioworks is one of the few domestic companies capable of full-process localized production of mRNA therapy drugs, enhancing its market position [6].

Core Viewpoint - The research team at Xi'an University of Electronic Science and Technology has developed a novel non-ionic delivery system that addresses the "toxicity-efficiency" dilemma in mRNA therapy, enhancing safety and efficacy in gene therapy applications [1][2]. Group 1: Technology Overview - The new delivery system, termed TNP, utilizes thiourea groups to form strong hydrogen bond networks with mRNA, allowing for efficient loading without charge dependence, unlike traditional lipid nanoparticles (LNP) [2]. - TNP significantly extends the in vivo expression duration of mRNA to seven times that of LNP, improves targeting efficiency to the spleen, and achieves a near 100% cell survival rate, indicating high biocompatibility [2][3]. Group 2: Mechanism of Action - TNP employs a unique intracellular transport mechanism that avoids the Rab11-mediated recycling pathway, achieving a high intracellular retention rate of 89.7%, compared to only 27.5% for LNP [2]. - The interaction between thiourea groups and endosomal membrane lipids induces membrane permeabilization, allowing for the direct release of intact mRNA into the cytoplasm, thus circumventing lysosomal degradation [2]. Group 3: Implications for Gene Therapy - The innovative non-ionic delivery technology is expected to lower the costs of gene therapy, making treatments more accessible for patients with rare and chronic diseases [3]. - The research team has already developed multiple targeted delivery systems based on this technology, which are currently in animal testing phases for applications in tumor immunotherapy and gene editing for rare diseases [3].