Engineering IL-10 and rapamycin to bind collagen leads to improved anti fibrotic efficacy in lung and kidney fibrosis

• Published in: Scientific reports Vol. 15; no. 1; pp. 13279 - 15
• Main Authors: White, Michael J. V., Raczy, Michal M., Budina, Erica, Yuba, Eiji, Solanki, Ani, Shim, Ha-Na, Zhang, Zheng Jenny, Gray, Laura T., Cao, Shijie, Alpar, Aaron T., Hubbell, Jeffrey A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.04.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/152; 631/250/256/2515; 692/308/153; 692/4022/1585/3182; 692/699/1785; Animal models; Animals; Collagen; Collagen - metabolism; Collagen-targeting; Decorin; Disease Models, Animal; Drug delivery; Drug Delivery Systems; Extracellular matrix; Fibrosis; Fibrosis - drug therapy; Humanities and Social Sciences; Humans; Interleukin 10; Interleukin-10 - genetics; Interleukin-10 - metabolism; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney Diseases - drug therapy; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidneys; Lung - drug effects; Lung - metabolism; Lung - pathology; Mice; Mice, Inbred C57BL; Micelles; Molecules; multidisciplinary; Public health; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Rapamycin; Science; Science (multidisciplinary); Sirolimus - administration & dosage; Sirolimus - metabolism; Sirolimus - pharmacology; Von Willebrand factor; von Willebrand Factor - metabolism; Drug delivery; Rapamycin; Interleukin-10; Collagen-targeting; Fibrosis
• DOI: 10.1038/s41598-025-94073-3
• ISSN: 2045-2322

Fibrotic diseases are involved in 45% of deaths in the United States. In particular, fibrosis of the kidney and lung are major public health concerns due to their high prevalence and lack of existing treatment options. Here, we harness the pathophysiological features of fibrotic diseases, namely leaky vasculature and aberrant extracellular matrix (ECM) protein deposition (i.e. collagen), to target an anti-fibrotic biologic and a small molecule drug to disease sites of fibrosis, thus improving the therapeutic potential of both the biologic and small molecule in mouse models of both lung and kidney fibrosis. First, we identify and validate two collagen-targeting drug delivery systems that preferentially accumulate in fibrotic organs: von Willebrand Factor’s A3 domain (VWF-A3) and decorin-derived collagen-binding peptide-conjugated micelles (CBP-micelles). We then engineer and recombinantly express novel candidate biologic therapies based on the anti-inflammatory cytokine IL-10: A3-IL-10 and A3-Serum Albumin-IL-10 (A3-SA-IL-10). Simultaneously, we stably encapsulate the potential anti-fibrotic water-insoluble drug, rapamycin, in CBP-micelles. We show that these novel formulations of therapeutics bind to collagen in vitro and that their efficacy in mouse models of lung and kidney fibrosis is improved, compared to free, untargeted drugs. Our results demonstrate that collagen-targeted anti-fibrotic drugs may be next generation therapies of high clinical potential.