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].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 嵌合抗原受体巨噬细胞 （CAR-M） 疗法在实体瘤治疗中展现出巨大潜力；然而，CAR-M 在免疫抑制性肿 瘤微环境中的表型再驯化限制了其抗肿瘤免疫能力。 2025 年 4 月 29 日，山东大学 姜新义 教授、 史本康 教授、 荆卫强 等人在 Nature 子刊 Nature Cancer 上发 表了题为： An in situ engineered chimeric IL-2 receptor potentiates the tumoricidal activity of proinflammatory CAR macrophages in renal cell carcinoma 的研究论文。 该研究开发了一种新型 原位 CAR-M 细胞疗法 ，通过原位工程化的嵌合 IL-2 受体增强 CAR-M 细胞的的肿 瘤杀伤活力，用于肾细胞癌的治疗。 论文链接 ： 在这项最新研究中，研究团队报告了一种原位工程化的嵌合白介素（IL）-2 信号受体 （CSR） ，用于可控 地调节嵌合抗原受体巨噬细胞 （CAR-M） 的促炎表型，增强其持续的抗肿瘤免疫能力。 具体而言，研究团队定 ...