Tissue-resident macrophages are essential regulators of health, orchestrating immune defence, tissue repair, inflammation, and iron homeostasis. Consequently, dysfunction of these highly specialised cells contributes to the pathogenesis of a wide range of diseases, including chronic inflammatory disorders, infectious diseases, and conditions associated with impaired iron metabolism. Despite their therapeutic potential, selectively targeting disease-driving macrophage populations while sparing healthy macrophages in other tissues remains a major challenge for conventional drugs and systemically delivered biologics. Precision delivery technologies capable of targeting specific macrophage subsets in vivo could therefore unlock new opportunities for RNA therapeutics across diverse disease settings.
Here, we present Mac-LNPs, a macrophage-targeted lipid nanoparticle platform that enables selective delivery of RNA therapeutics to tissue-resident macrophages without the need for post-formulation functionalisation. Rather than relying on surface modification with antibodies or peptides after nanoparticle assembly, macrophage specificity and tissue tropism are encoded directly into the LNP formulation itself. This simplifies manufacturing, avoids RNA damage and losses associated with additional processing steps, and maintains compatibility with established, scalable LNP production workflows. Using a luciferase reporter, we confirmed tissue-specific mRNA expression in the lungs or spleen of WT C57B/6 mice, just 7h post intranasal or intravenous LNP administration, respectively. More importantly, using a transgenic Cre-reporter mouse model, we have demonstrated that we can precisely target disease-relevant macrophage populations in these organs.
To evaluate the therapeutic potential of our platform, we have successfully applied our lung-targeted Mac-LNPs to rewire programmed cell death signalling in alveolar macrophages infected with Mycobacterium tuberculosis (Mtb), inducing apoptosis and promoting pathogen clearance in vivo. Building on this success, we are now exploring the versatility of our Mac-LNPs beyond infectious diseases, applying them to chronic obstructive pulmonary disease (COPD) driven by pathogenic lung macrophages, as well as anaemia of inflammation driven by impaired red pulp macrophages in the spleen.
Collectively, these studies establish Mac-LNPs as a broadly applicable RNA delivery platform capable of selectively targeting disease-driving macrophage populations across multiple tissues. By combining cell-type specificity, tissue selectivity, scalable manufacturing and therapeutic efficacy, Mac-LNPs provide a powerful new strategy for genetic reprogramming of macrophages in vivo, opening the door to precision RNA medicines for infectious, inflammatory and metabolic diseases.