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Antifibrotic monocyte activation by nanoparticles resolves murine pulmonary fibrosis
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DOI：10.1016/j.biomaterials.2026.124388.png)
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Abstract
En 中文
Organ fibrosis presents a substantial disease burden with few therapeutic options. Innate immunity mediates fibrinogenesis, but also plays a major role in fibrinolysis. Here, we show that immunomodulatory nanoparticles (NPs) can harness this endogenous antifibrotic capacity by catalyzing monocyte activation leading to resolution of bleomycin-induced pulmonary fibrosis in vivo. Cargo-free NPs comprised of the degradable biopolymer poly(lactide-co-glycolide) (PLG) induce a transcriptional shift toward antifibrotic immune activation in profibrotic M2 macrophages (MΦs) in vitro. NPs stimulate M2 MΦs toward a glycolytic, rather than fatty acid oxidative, metabolism; suppress canonical M2 markers like arginase-1 (Arg1) and periostin ( ); and upregulate collagenases, hyaluronidases and immunoregulatory factors. When delivered intravenously in vivo, NPs resolve established bleomycin-induced pulmonary fibrosis and invert the trajectory of over 1000 genes from pre- to post-treatment according to bulk RNA-sequencing. NPs also suppress profibrotic signaling and increase expression of repair-associated pathways like peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear retinoic acid receptor (RAR), vascular endothelial growth factor (VEGF), and sphingolipid signaling in fibrotic lungs. Flow cytometry confirms that NPs induce monocyte recruitment to fibrotic lungs via enhanced integrin expression. Altogether, NPs induce a robust pro-regenerative signature comprised of ECM degradation, inflammation resolution, and tissue repair pathways, concomitant with increased NP+ monocyte recruitment to fibrotic lungs. This work demonstrates that monocytes are not intrinsically profibrotic, but rather, their effects are context-dependent, and they retain a capacity for fibrotic resolution under conditions that can be induced by materials with translational potential.
Keywords:
Immunoengineering
Nanoparticles
Immunomodulation
Fibrosis
Inflammation
Major-Biological sciences
Minor-Immunology and Inflammation
Journal
IF:
12.9
Papers:
1.9W
Citations:
10.8W