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MACROPHAGE CELL THERAPY WITH FIBROSIS CLEARING FUNCTION ENABLED BY BIOMATERIALS
Journal article   Peer reviewed

MACROPHAGE CELL THERAPY WITH FIBROSIS CLEARING FUNCTION ENABLED BY BIOMATERIALS

K.L. Spiller and T. Tylek
Cytotherapy (Oxford, England), v 28(5), 102191
May 2026
DOI: https://doi.org/10.1016/j.jcyt.2026.102191
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Abstract

Biomaterials Fibrosis Macrophage
There are currently no therapies that can clear established fibrosis. Macrophages are one of the only cell types capable of remodeling fibrotic tissue into functional tissue, but macrophage cell therapy has been limited by two main challenges: 1) It is not known how to pharmacologically induce a functionally fibrosis-resolving phenotype. 2) Macrophages are highly plastic cells that rapidly shift phenotype in response to microenvironmental cues, so a strategy is needed to maintain a desired phenotype in situ. Many cell engineering strategies involving gene editing suffer from high manufacturing costs and regulatory complexity, and they are typically pro-inflammatory. The goal of this study was to design a biomaterial-mediated strategy to control transplanted macrophages in situ, while streamlining manufacturing and improving phenotypic control. Macrophages were loaded ex vivo via phagocytosis with polymeric microparticles composed of poly(lactic-co-glycolic acid) (PLGA) that slowly release the glucocorticoid dexamethasone intracellularly to generate microparticle-loaded macrophages (Dex-MP-macs). Fibrosis-clearing function was measured in vitro using the DQ collagen assay and in vivo in the murine repetitive bleomycin model of pulmonary fibrosis. Dex-MP-macs or controls were administered 6 weeks after the last bleomycin dose, when fibrosis was well established and incapable of spontaneous resolution. Dex-MP-macs upregulated collagen-degrading function in vitro, unlike macrophages treated with soluble dexamethasone, suggesting a novel synergistic effect of the intracellular delivery of dexamethasone and phagocytosis of degradable microparticles (Fig. 1a). In vivo, a single dose of Dex-MP-macs caused a 28% reduction in total collagen content within 1 week compared to pre-treatment levels, indicating true clearance of fibrotic tissue as opposed to attenuation of fibrotic progression. By 2 weeks, Dex-MP-macs caused a 54% reduction in total fibrotic tissue volume as measured by microCT (Fig. 1b). In contrast, fibrosis was not influenced by the control groups, which included unmodified macrophages (Unmod-macs), macrophages loaded with blank MPs (Blank-MP-macs), free dexamethasone-releasing microparticles (free Dex MPs), systemic dexamethasone, and systemic nintedanib, the main drug used to treat idiopathic pulmonary fibrosis (IPF). This novel biomaterial-enabled macrophage cell therapy holds potential to clear established fibrotic tissue in the lungs.

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