Pulmonary macrophages are potent immune mediators essential for lung tissue repair and form the first line of defence against inhaled pollutants and pathogens. However, dysregulation of their function turns these protectors into malignancies, perpetuating inflammation and lung damage in various indications, including chronic obstructive pulmonary disease, cystic fibrosis, non-small cell lung cancers and respiratory infections. Despite their prominent role in lung pathology, targeting this critical but small cell population within the lung by traditional means is challenging. Systemic administration of small-molecule drugs often requires high doses and can lead to adverse effects in healthy tissue.
To address this lack of specificity, we have developed a lipid nanoparticle (LNP) platform for the precise delivery of RNA therapeutics to pulmonary macrophages in vivo, without overt toxicity.
Our novel LNP formulation selectively targets macrophages with high specificity and increased RNA uptake compared to commercially available LNPs in vitro. Using a luciferase reporter mRNA, we have confirmed selective biodistribution to the lungs of WT C57Bl/6 mice just 7 hours after either intranasal or intravenous administration of the LNPs. More specifically, using a transgenic Cre-reporter mouse model, we have demonstrated that our LNP platform can selectively target alveolar macrophages and/or interstitial macrophages individually, thereby further fine-tuning our therapeutic approach for in vivo application. By leveraging this versatile delivery platform, we successfully rewired programmed cell death signalling pathways to induce apoptosis in alveolar macrophages infected with Mycobacterium tuberculosis (Mtb), thereby promoting pathogen clearance in vivo. Building on this proof of principle, we are now investigating other lung conditions that could benefit from restoring normal pulmonary macrophage signalling to dampen inflammation, including chronic obstructive pulmonary disease (COPD), asthma, and long COVID.