Improving outcomes in intracerebral hemorrhage through microglia/macrophage-targeted IL-10 delivery with phosphatidylserine liposomes

Ranran Han; Xi Lan; Zheng Han; Honglei Ren; Safiya Aafreen; Wenshen Wang; Zhipeng Hou; Tianyue Zhu; Andrew Qian; Xiaoning Han; Raymond C Koehler; Guanshu Liu

doi:10.1016/j.biomaterials.2023.122277

Improving outcomes in intracerebral hemorrhage through microglia/macrophage-targeted IL-10 delivery with phosphatidylserine liposomes

Biomaterials. 2023 Oct:301:122277. doi: 10.1016/j.biomaterials.2023.122277. Epub 2023 Aug 15.

Authors

Ranran Han¹, Xi Lan¹, Zheng Han², Honglei Ren¹, Safiya Aafreen³, Wenshen Wang⁴, Zhipeng Hou⁵, Tianyue Zhu⁶, Andrew Qian⁶, Xiaoning Han⁷, Raymond C Koehler⁸, Guanshu Liu⁹

Affiliations

¹ Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
² Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, MD, USA; Center for Health Systems Innovation, Oklahoma State University, Stillwater, OK, 74078, USA.
³ Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁴ Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, MD, USA.
⁵ Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁷ Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. Electronic address: xhan15@jhmi.edu.
⁸ Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. Electronic address: rkoehler@jhmi.edu.
⁹ Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, MD, USA. Electronic address: gaunshu@mri.jhu.edu.

PMID: 37597297
DOI: 10.1016/j.biomaterials.2023.122277

Abstract

Intracerebral hemorrhage (ICH) remains the most lethal type of stroke, and effective clinical therapies that can speed up hematoma resolution after ICH are still lacking. While the beneficial effects of IL-10 on ICH recovery have been demonstrated, the clinical translation of IL-10 requires effective delivery methods by which sufficient IL-10 can be delivered to ICH-affected regions in the brain. Here we report the use of a phosphatidylserine (PS) liposome (PSL)-based nanoparticle system for microglia/macrophage-targeted delivery of IL-10 in ICH. We first prepared IL-10-conjugated PSL (PSL-IL10) and characterized their immunomodulating effects in vitro. Then we evaluated the therapeutic effects, including hematoma absorption, short-term outcomes, and neuroinflammation, of intranasally administered PSL-IL10 (3 μg IL-10 per mouse, 2 h post-ICH) in a collagenase-induced ICH mouse model. We also isolated microglia/macrophages from the mouse brains with ICH to analyze their morphology, phagocytosis ability, and polarization. Our study reveals that, 1) PSL-IL10 treatment resulted in significantly improved outcomes and accelerated hematoma resolution in the acute phase of ICH; 2) PSL-IL10 inhibited glial activation and down-regulated pro-inflammatory cytokine production; 3) PSL-IL10 induced Iba1⁺ cells with a stronger phagocytosis ability; 4) PSL-IL10 activated STAT3 and upregulated CD36 expression in microglia/macrophage. These findings collectively show that PSL-IL10 is a promising nanotherapeutic for effectively ameliorating ICH.

Keywords: IL-10; Intracerebral hemorrhage (ICH); Liposomes; Microglia and macrophage-targeted drug delivery; Phosphatidylserine--liposomes (PSL).

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Cerebral Hemorrhage / drug therapy
Hematoma
Interleukin-10*
Liposomes
Macrophages
Mice
Microglia*
Phosphatidylserines

Substances

Interleukin-10
Phosphatidylserines
Liposomes

Abstract

Publication types

MeSH terms

Substances

Grants and funding