用于哮喘治疗的非炎性脂质纳米粒沉默肺内积聚的黏液蛋白5AC
2026/04/02
摘要：
黏液蛋白5AC（MUC5AC）的过度表达驱动过量的黏液分泌和呼吸道阻塞，是导致严重哮喘和黏液阻塞性肺病（MOLDs）患者死亡的重要因素。虽然siRNA介导的MUC5AC表达沉默是治疗MOLDs的有效策略，但我们的研究发现，气管内给予美国食品药品监督管理局批准的脂质纳米粒（LNP）载体，会因其炎症副作用反而导致MUC5AC增加。为应对这一挑战，我们设计了用于哮喘治疗的非炎性LNP，具体通过以下方式实现：（I）开发具有低免疫原性的可离子化阳离子脂质；（Ⅱ）将抗炎天然化合物衍生物整合到LNP中；（Ⅲ）降低LNP制剂的N/P比。经过三轮筛选——评估基因沉默效率（体外和体内）、LNP物理化学特性和生物安全性——我们确定了一个领先候选制剂（制剂1），其在体内实现了85%的MUC5AC沉默效率，优于整合素αvβ6配体修饰的siRNA（69%），并且与SM102 LNP和MC3 LNP相比，生物安全性显著提高。在屋尘螨（HDM）诱导的哮喘小鼠模型中，siMuc5ac-LNP能有效缓解气道炎症和阻塞，并具有持续的预防效果。此外，制剂1在慢性阻塞性肺疾病（COPD）患者来源的类器官模型中也能有效抑制MUC5AC分泌。总而言之，我们开发了一个具有临床转化潜力的、非炎性的siRNA递送平台，对哮喘和其他MOLDs具有治疗潜力。
Lung-Accumulating Mucin 5AC Silencing by Noninflammatory Lipid Nanoparticles for Asthma Treatment
Zhao Z, Shan X, Wang W, Cao C, Chen D, Chu L, Zeng Y, Liu Y, Yang Y, Wu Y, Zhao Y, Chen J, Wang Z, Liu X, Chen Y, Lu X, Zhou J, Miao L, Luo C
Abstract
Overexpression of Mucin 5AC (MUC5AC) drives excessive mucus secretion and respiratory obstruction, contributing to mortality in severe asthma and mucous obstructive lung diseases (MOLDs). While siRNA-mediated silencing of MUC5AC expression represents an effective strategy to treat MOLDs, our investigation reveals that intratracheal administration of FDA-approved lipid nanoparticle (LNP) carriers can paradoxically lead to MUC5AC increases due to inflammatory side effects. To address this challenge, we designed noninflammatory LNPs for asthma treatment by (I) developing ionizable cationic lipids with low immunogenicity, (II) incorporating anti-inflammatory natural compound derivatives into LNPs, and(Ⅲ) reducing the N/P ratio of LNP formulations. After three rounds of screening-evaluating gene silencing efficiency (in vitro and in vivo), LNP physicochemical properties and biosafety─we identify a lead candidate formulation (Formulation 1) that achieves 85% MUC5AC silencing efficiency in vivo, outperforming the integrin αvβ6 ligand-modified siRNA (69%), and demonstrates notably improved biosafety when compared to SM102 LNPs and MC3 LNPs. In house dust mite (HDM)-induced asthmatic mice, siMuc5ac-LNPs effectively alleviate airway inflammation and obstruction with a sustained preventive effect. Moreover, Formulation 1 effectively suppresses MUC5AC secretion in a Chronic Obstructive Pulmonary Disease (COPD) patient-derived organoid model. Collectively, we develop a clinically translatable, noninflammatory siRNA delivery platform with therapeutic potential for asthma and other MOLDs.
黏液蛋白5AC（MUC5AC）的过度表达驱动过量的黏液分泌和呼吸道阻塞，是导致严重哮喘和黏液阻塞性肺病（MOLDs）患者死亡的重要因素。虽然siRNA介导的MUC5AC表达沉默是治疗MOLDs的有效策略，但我们的研究发现，气管内给予美国食品药品监督管理局批准的脂质纳米粒（LNP）载体，会因其炎症副作用反而导致MUC5AC增加。为应对这一挑战，我们设计了用于哮喘治疗的非炎性LNP，具体通过以下方式实现：（I）开发具有低免疫原性的可离子化阳离子脂质；（Ⅱ）将抗炎天然化合物衍生物整合到LNP中；（Ⅲ）降低LNP制剂的N/P比。经过三轮筛选——评估基因沉默效率（体外和体内）、LNP物理化学特性和生物安全性——我们确定了一个领先候选制剂（制剂1），其在体内实现了85%的MUC5AC沉默效率，优于整合素αvβ6配体修饰的siRNA（69%），并且与SM102 LNP和MC3 LNP相比，生物安全性显著提高。在屋尘螨（HDM）诱导的哮喘小鼠模型中，siMuc5ac-LNP能有效缓解气道炎症和阻塞，并具有持续的预防效果。此外，制剂1在慢性阻塞性肺疾病（COPD）患者来源的类器官模型中也能有效抑制MUC5AC分泌。总而言之，我们开发了一个具有临床转化潜力的、非炎性的siRNA递送平台，对哮喘和其他MOLDs具有治疗潜力。
（中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校）
（ACS Nano. 2026 Mar 24; DOI: 10.1021/acsnano.5c16693）
（ACS Nano. 2026 Mar 24; DOI: 10.1021/acsnano.5c16693）
Lung-Accumulating Mucin 5AC Silencing by Noninflammatory Lipid Nanoparticles for Asthma Treatment
Zhao Z, Shan X, Wang W, Cao C, Chen D, Chu L, Zeng Y, Liu Y, Yang Y, Wu Y, Zhao Y, Chen J, Wang Z, Liu X, Chen Y, Lu X, Zhou J, Miao L, Luo C
Abstract
Overexpression of Mucin 5AC (MUC5AC) drives excessive mucus secretion and respiratory obstruction, contributing to mortality in severe asthma and mucous obstructive lung diseases (MOLDs). While siRNA-mediated silencing of MUC5AC expression represents an effective strategy to treat MOLDs, our investigation reveals that intratracheal administration of FDA-approved lipid nanoparticle (LNP) carriers can paradoxically lead to MUC5AC increases due to inflammatory side effects. To address this challenge, we designed noninflammatory LNPs for asthma treatment by (I) developing ionizable cationic lipids with low immunogenicity, (II) incorporating anti-inflammatory natural compound derivatives into LNPs, and(Ⅲ) reducing the N/P ratio of LNP formulations. After three rounds of screening-evaluating gene silencing efficiency (in vitro and in vivo), LNP physicochemical properties and biosafety─we identify a lead candidate formulation (Formulation 1) that achieves 85% MUC5AC silencing efficiency in vivo, outperforming the integrin αvβ6 ligand-modified siRNA (69%), and demonstrates notably improved biosafety when compared to SM102 LNPs and MC3 LNPs. In house dust mite (HDM)-induced asthmatic mice, siMuc5ac-LNPs effectively alleviate airway inflammation and obstruction with a sustained preventive effect. Moreover, Formulation 1 effectively suppresses MUC5AC secretion in a Chronic Obstructive Pulmonary Disease (COPD) patient-derived organoid model. Collectively, we develop a clinically translatable, noninflammatory siRNA delivery platform with therapeutic potential for asthma and other MOLDs.
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过敏性鼻炎与哮喘患者对NPP-SLIT疗法的感知获益：ERAPP真实世界队列研究初步结果
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儿科急诊用于哮喘急性发作的皮质类固醇药物的差异：一项PECARN注册研究
