✦ Volume 4 Issue 9 ✦
封面解读
刘泽众/陆路
The emergence of β-coronaviruses underscores the urgent need for broadly protective mucosal vaccines that block infection at the respiratory entry site. However, intranasal vaccination remains limited by mucosal barriers, rapid antigen clearance, and inefficient multivalent antigen presentation. We developed a STING agonist-adjuvanted intranasal vaccine based on size-optimized gold nanoparticles (AuNPs), co-displaying six β-coronavirus receptor-binding domains selected based on serotypic diversity in a mosaic configuration (AuNP-Mix). In mice, AuNP-Mix enhanced mucosal penetration and prolonged lung retention, eliciting cross-neutralizing antibody responses against SARS-CoV-2, SARS-related coronaviruses, and MERS-related coronaviruses. The cover portrays the lung mucosa as a fortified immune frontline, where retained multivalent AuNPs sustain immune stimulation. This promotes tissue-resident memory T cells (TRM) and secretory IgA (sIgA), together forming a pulmonary immune barrier against viral invasion and highlighting its potential for broad-spectrum mucosal vaccination.
✦ All Papers ✦
1. Recollections of an open U.S.–China anti-hantaviral clinical trial in the 1980s
通信作者：郑志明
Recent incidence of hantavirus pulmonary syndrome on a Dutch cruise ship, MV Hondius, traveling in the South Atlantic Ocean, led to health authorities across several countries racing to trace and contain an outbreak. In mid-December 1985, the Ministry of Health of the People’s Republic of China, the Department of Defense of United States of America, and the U.S. Food and Drug Administration approved a proposed study entitled “Double-blind, placebo-controlled clinical trial of ribavirin therapeutic efficacy in the treatment of epidemic hemorrhagic fever (EHF).” The project was led by John Huggins of the U.S. Army Medical Research Institute of Infectious Diseases and by Zhi-Ming Zheng and Chin-Min Hsiang of VRIHMC as co-principal investigators. According to Dr. Minzhang Chen, the late Minister of Health of the PRC, this project represented the largest medical research collaboration between China and the U.S. up to that time and the first double-blind, placebo-controlled clinical trial ever conducted in China.
引用：
Zheng ZM. Recollections of an open U.S.–China anti-hantaviral clinical trial in the 1980s. hLife 2026; 4: 525–528.
2. Engineering organoids toward implantable living therapeutics
通信作者：尤晓颜、王慧、王汉杰
本文系统梳理了活体类器官从体外构建到体内移植的工程策略与转化路径。重点从工程技术角度深入探讨了四大赋能领域。水凝胶工程的核心在于给类器官搭个“好房子”，通过构筑可调的生化信号、力学性能、降解性与动态重塑能力，调节类器官生长分化；微流控芯片重在高通量与精确调控的双重突破；3D生物打印能按器官的生理结构“定制打印”，比如肝小叶的分区代谢功能，或者大面积组织缺损的修复支架；合成生物学则侧重改写类器官的“内在程序”。多学科技术加持下，类器官从体外模型迈向植入治疗物取得了让人振奋的成果。工程化皮肤类器官已成功长出含毛囊的完整皮肤；血管化肝类器官恢复了肝硬化小鼠约93%的肝功能，并重建了肝小叶结构；工程化肝类器官可调节甲状腺激素水平，改善肝纤维化与糖尿病；工程化米色脂肪类器官可显著改善高脂饮食诱发肥胖和2型糖尿病小鼠的代谢紊乱。这些进展表明，多学科赋能类器官从概念验证正在迈向临床应用。
引用：
Shi Z, Yang Q, You X, et al. Engineering organoids toward implantable living therapeutics. hLife 2026; 4: 529–553.
3. Establishing a regulatory framework for phage therapy in China
朱同玉/乐率观点文章上线！打通中国噬菌体治疗监管落地“最后一公里”
通信作者：吴楠楠、乐率、朱同玉
抗生素耐药性正对现代医学构成日益严重的威胁。据预测，2025至2050年间，耐药菌感染将导致超过3900万人死亡，并造成百万亿美元的经济损失。在此背景下，具备精准杀菌能力的噬菌体疗法，正从“最后的治疗选择”迈向规范化临床转化的关键阶段。然而，全球范围内共同面临两大瓶颈：一是噬菌体制品的质量要求缺乏统一标准，二是其审批路径与监管要求尚不明确。这些问题已成为抢占这一新兴赛道制高点的核心掣肘。本文根据《生物医学新技术临床研究和临床转化应用管理条例》（国务院令第818号）和《中华人民共和国药品管理法实施条例》（国务院令第828号），系统梳理了开展噬菌体治疗临床研究、转化应用及药物开发的监管路径。同时，结合全球主要国家的噬菌体治疗监管现状，在具体实施细节上提出了参考建议，旨在探索并走出一条符合中国国情的噬菌体治疗高质量发展道路，为“健康中国”战略提供支撑。
引用：
Yang J, Chen H, He X, et al. Establishing a regulatory framework for phage therapy in China. hLife 2026; 4: 554–557.
4. Intranasal gold nanoparticle-antigen induces mucosal and systemic immunity against β-coronaviruses
hLife | 复旦大学刘泽众/陆路团队设计新型呼吸道病毒黏膜疫苗，构筑广谱黏膜免疫防线
通信作者：陆路、刘泽众
蛋白纳米颗粒作为多价抗原展示的有效载体，在诱导强效且广谱的免疫保护方面显示出显著潜力。然而，传统蛋白纳米颗粒骨架可能诱导非目标骨架特异性B细胞，并与目标抗原特异性B细胞竞争，造成抗原免疫分流。另一方面，固定的颗粒尺寸难以跨越复杂的呼吸道生理屏障，难以实现高效的黏膜抗原递送与免疫激活。本研究设计了一种金属纳米颗粒作为多价黏膜疫苗底盘，通过粒径优化，“马赛克”共展示多种冠状病毒抗原，有效延长抗原滞留，突破呼吸道生理屏障，从而为激发机体强效且广谱的黏膜与系统性免疫创造了条件。这一策略不仅有望阻断病毒在入侵门户处的感染，还为应对未来可能出现的新型β冠状病毒提供了可扩展的技术路径。
引用：
Wang M, Wang W, Xu W, et al. Intranasal gold nanoparticle-antigen induces mucosal and systemic immunity against β-coronaviruses. hLife 2026; 4: 558–580.
hLife | 给噬菌体装上"信号灯"，实现肺炎克雷伯菌快速荚膜分型
通信作者：冯婕
肺炎克雷伯菌（Klebsiella pneumoniae）是医院感染和尿路感染中的重要机会致病菌，其荚膜多糖不仅帮助细菌逃避免疫清除，也是区分不同菌株、追踪流行传播和制定疫苗或治疗策略的关键标志。传统血清学分型依赖抗血清，存在成本高、周期长、批次差异大等局限；PCR或测序方法无法区分活菌与死菌。因此，面向临床场景的快速、灵敏和可扩展荚膜分型方法仍然十分必要。本研究建立了一套基于发光报告噬菌体的平台，将NanoLuc荧光素酶报告基因导入K2型特异噬菌体ΦRCIP0109，获得ΦRCIP0109::nluc。这项工作展示了将噬菌体天然特异性转化为诊断优势的可行路径。样本前处理和检测流程相对简洁，有利于后续向临床检验等场景转化。未来若结合更多RBP资源、机器学习预测和蛋白设计，可继续扩展到更多荚膜型和其他重点病原体。其快速、特异、可模块化扩展的特点，有望服务于感染监测、精准用药和噬菌体治疗方案选择。
引用：
Song Y, Jing S, Li Y, et al. A phage-based luminescent reporter platform for rapid typing of multiple capsular types of Klebsiella pneumoniae. hLife 2026; 4: 581–595.
通信作者：Stanley Perlman、肇静娴、赵金存、庄珍
Human coronaviruses remain a continuing public health challenge because antigenically distinct viruses circulate in humans, while related animal coronaviruses retain zoonotic potential. A central unresolved issue, however, is how to distinguish conserved epitopes that merely enable ex vivo cross-recognition from those that can be translated into protective immunity in vivo. This study refines the concept of coronavirus T-cell cross-immunity. Conserved N epitopes induce airway CD4⁺ T cells with antiviral effector properties and protection against selected viruses. Cross-recognition is not equivalent to cross-protection. Protective T-cell targets may satisfy conservation across viruses, efficient processing and presentation during infection, immunological dominance, and localization to the tissue in which viral replication occurs. This study has immediate implications for pan-coronavirus vaccine design.
引用：
Lai X, Chen Z, Zhao S, et al. Conserved nucleocapsid epitopes induce cross-reactive CD4⁺ T-cell responses with selective protection against human coronaviruses in mice. hLife 2026; 4: 596–600.
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