EVALUATING THE ABILITY OF β-GLUCAN AND RP-182 DERIVED NANOPARTICLES TO MODULATE MACROPHAGES AS POTENTIAL LUNG FIBROSIS THERAPEUTICS

Abstract

Pulmonary Fibrosis is a progressive and fatal lung disease characterized by excessive extracellular matrix deposition leading to aberrant thickening and scarring of the lungs. Current therapies include Pirfenidone and Nintedanib, which slow but do not stop disease progression, underscoring the need for new treatment strategies. Macrophages are central regulators of tissue homeostasis, immunity, and repair. In the fibrotic lung, they become aberrantly activated and perpetuate fibrosis by driving fibroblast activation and ECM accumulation. Their high plasticity and receptor diversity make them attractive therapeutic targets for immunomodulatory nanomedicines. We evaluated three nanoparticle platforms designed to modulate macrophage function in the context of pulmonary fibrosis. The first two employed -glucan, a Dectin-1 agonist with known immunostimulatory activity, formulated as polyelectrolyte complexes and self-assembled nanoparticles. The third utilized RP-182, a synthetic peptide reported to bind to the mannose receptor CD206, conjugated onto a polystyrene nanoparticle. To assess these platforms, bone marrow-derived macrophages were used to understand dose-dependent effects on phenotype and uptake. Precision-cut lung slices provided a multicellular ex vivo approach to assess gene expression through RT-qPCR. -glucan nanoparticles, especially the self-assembled platform, induced a shift in BMDM phenotype toward pro-inflammatory, increasing surface expression of MHCII and CCR2 and transcription of Tnf in our PCLS model. In contrast, RP-182 conjugated nanoparticles failed to alter macrophage phenotype, where the increase in pro-inflammatory markers and preferential nanoparticle uptake observed were a result of the polystyrene vehicle. These findings demonstrate that ligand choice and nanoparticle composition critically shape macrophage response. Overall, this work emphasizes the need to couple effective