Lung-Accumulating Mucin 5AC Silencing by Noninflammatory Lipid Nanoparticles for Asthma Treatment

Mar 9, 2026ACS nano

Using Safe Lipid Nanoparticles to Reduce Lung Mucin 5AC for Asthma Treatment

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Intratracheal administration of a novel lipid nanoparticle formulation achieves 85% MUC5AC silencing efficiency in vivo.

Overexpression of MUC5AC is linked to excessive mucus secretion and respiratory issues in severe asthma and mucous obstructive lung diseases.
Traditional lipid nanoparticle carriers can paradoxically increase MUC5AC levels due to inflammatory responses.
Noninflammatory lipid nanoparticles were developed by creating low-immunogenicity cationic lipids and incorporating anti-inflammatory compounds.
The lead candidate formulation outperformed a modified siRNA in terms of MUC5AC silencing efficiency.
In an animal model of asthma, lipid nanoparticles reduced airway inflammation and obstruction effectively.
Formulation 1 also decreased MUC5AC secretion in a model derived from Chronic Obstructive Pulmonary Disease patients.

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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,-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. siMuc5ac