撰文丨王聪 编辑丨王多鱼 排版丨水成文 免疫疗法 彻底改变了肿瘤治疗的临床模式。靶向 PD-1/PD-L1 的免疫检查点抑制剂 （ICI） 持续获得美国 FDA 批准，用于肿瘤的单药治疗和联合治疗。然而， 这些方法在晚期肿瘤患者中的临床获益有限。总体而言，晚期肿瘤的体细胞突变率低，浸润淋巴细胞少，PD-L1 表达水平低，这些特征表明肿瘤在免疫学上属 于"冷肿瘤"。 已发现多种免疫细胞因子可调控 T 细胞的扩增、存活和功能，其中包括 IL-2、IL-7、IL-12 和 IL-15，它们有望 将"冷肿瘤"转化为"热肿瘤"，与免疫检查点抑 制剂协同作用，可增强抗肿瘤反应。 然而，它们在临床上的应用受到诸多技术难题、安全性顾虑、多效性影响以及在晚期肿瘤中观察到的疗效欠佳等因素的阻碍。尽管已开发出多种策略来增强它们 的、靶向性或联合治疗，但高昂的合成和产品生产成本、有限的持久性以及预期疗效不足，需要进一步改进策略来充分发挥免疫细胞因子和免疫检查点抑制剂联 合治疗的潜力。 2025 年 10 月 10 日，陆军军医大学 连继勤 、 邹全明 、 杨明珍 作为通讯作者（牛顿等人为第一作者）在 Cell 子刊 Cell Rep ...

Group 1 - The core viewpoint of the news is the collaboration between Baiaosaitu and Merck to evaluate antibody-conjugated lipid nanoparticles (Ab-LNP) for new applications in nucleic acid drug delivery, highlighting the strong interest in "precise delivery" in the biopharmaceutical sector [1][5] - The nucleic acid drug market is rapidly growing, with mRNA therapies gaining mainstream acceptance, but the delivery of nucleic acids remains a significant bottleneck [2][5] - The global lipid nanoparticle (LNP) market is projected to grow from $1.1 billion in 2025 to $3.5 billion by 2034, with a compound annual growth rate (CAGR) of 13.3% [2] Group 2 - Antibody-modified LNPs have shown promising results in animal models, significantly improving delivery efficiency to non-liver tissues, which is crucial for treating various diseases [2][3] - The partnership between Baiaosaitu and Merck marks the third deepening of their collaboration, indicating a new phase in the "antibody × delivery" model [4] - The trend towards platform and modular design in LNP technology is emerging, with new molecular forms like antibodies and bispecific antibodies expanding delivery capabilities [4] Group 3 - The investment landscape is shifting towards antibody-conjugated LNPs as a potential solution to the delivery bottleneck in nucleic acid drugs, with significant capital being directed into this area [3][5] - The collaboration between Baiaosaitu and Merck reflects the increasing involvement of Chinese biotech companies in the global restructuring of drug delivery technologies [5]

Core Viewpoint - The article discusses the development of a peptide-encoded organ-selective targeting (POST) method that enhances the delivery of mRNA to extrahepatic organs using lipid nanoparticles (LNP) [4][11]. Group 1: mRNA Delivery and LNP Technology - mRNA-based gene and protein replacement technologies present significant opportunities for vaccine, cancer treatment, and regenerative therapy development [2]. - LNPs have been widely adopted as delivery vehicles for mRNA COVID-19 vaccines, demonstrating their safety and efficacy [2]. - Achieving organ-selective delivery of LNPs containing mRNA remains challenging, particularly for extrahepatic organs [2][4]. Group 2: Advances in Organ-Selective Delivery - Recent studies have made progress in organ-selective delivery through simple binary charge modulation and lipid chemical modifications, but these strategies are limited by the rational design of the LNP-environment interface [2][4]. - The POST method utilizes specific amino acid sequences to engineer the surface of LNPs, allowing for efficient mRNA delivery to extrahepatic organs after systemic administration [4][7]. Group 3: Mechanism and Applications - The targeting mechanism of the POST system is based on the optimization of the mechanical affinity between peptide sequences and plasma proteins, forming a specific protein corona around the LNPs [4][9]. - The POST code does not rely on the charge of LNPs for organ selectivity, but rather on the unique protein corona formed, which is influenced by the amino acid sequence [9]. - The POST code is applicable to various LNP formulations and can facilitate the selective delivery of mRNA to organs such as the placenta, bone marrow, adipose tissue, and testes [9][11]. Group 4: AI and Computational Design - The research team developed an AI-based framework using a Transformer-based protein language model to generate peptide sequences with high mechanical affinity for specific proteins, demonstrating the potential of computational design in guiding LNP organ targeting [9][11]. - The peptide sequence RRRYRR was shown to enable selective delivery of mRNA to the lungs, supporting the feasibility of using computer-aided rational design for POST-LNP organ-selective delivery [9][11].

Core Viewpoint - The development of mRNA and lipid nanoparticles (LNP) has shown significant clinical success in delivering gene drugs to the liver, but the tendency of LNP to accumulate in the liver poses a major bottleneck for broader applications in gene therapy [2][4]. Group 1: Research Development - A collaborative research paper titled "Tissue-specific mRNA delivery and prime editing with peptide–ionizable lipid nanoparticles" was published in Nature Materials, showcasing a new platform for organ-targeted mRNA delivery [3]. - The research combines peptides and ionizable lipids to create a novel material called peptide-ionizable lipid (PIL), establishing a platform (PILOT) for organ-specific and tunable mRNA delivery [4][5]. Group 2: Engineering and Design - Researchers have invested significant effort into engineering mRNA-LNP to reach organs beyond the liver, utilizing ligand coupling, component optimization, and the development of new ionizable lipids [7]. - The study highlights the importance of ionizable lipids in determining the efficacy and organ selectivity of LNP, with a focus on customizing lipid structures through combinatorial chemistry [7][8]. Group 3: Synthesis and Modifications - The research team developed over 120 structurally diverse PILs using solid-phase supported synthesis (SPSS), which offers advantages over traditional liquid-phase synthesis [9]. - Specific modifications to amino acids, such as lysine and arginine, enhance mRNA delivery to the lungs, while cysteine and histidine modifications target the liver [11]. Group 4: Efficacy and Safety - The PILOT platform demonstrated effective delivery of Cre mRNA, achieving specific gene editing in targeted tissues, with editing efficiencies of 13.1% in the liver and 7.4% in the lungs [13]. - The study provides a universal design strategy for developing organ-targeted ionizable lipids, indicating the potential of the PILOT LNP platform in advancing organ-specific gene editing therapies [15].

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 ...