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Reprogramming Retinal Microglia Polarization by Efferocytosis-Mimicking Nanoparticles for Ameliorating Diabetic
Zhipeng Li1, Wenyu Wang2, Liping Zhu3
1School of Medicine, Weifang University of Science and Technology, Weifang 262700, China.
Abstract:
Diabetic retinopathy (DR), as the most common microvascular complication of diabetes, seriously threatens the vision of diabetic patients. As the resident phagocytes of the retina, microglia participate in inflammation, neovascularization, and neurodegeneration of DR. Herein, apoptotic retinal cell membrane-coated, rapamycin-loaded mesoporous Prussian blue NPs as immunomodulators for ameliorating DR by modulating microglial polarization are reported. The apoM@mPB@Ra NPs exhibited favorable stability and biocompatibility and achieved active targeted delivery due to the specific recognition between "eat me" signal expressed on apoptotic membrane and microglia. In an LPS-induced cellular inflammation model, apoM@mPB@Ra NPs effectively promoted microglial polarization toward the anti-inflammatory phenotype (M2) by scavenging intracellular reactive oxygen species (ROS) combined with affecting the mTOR signaling pathway, leading to downregulation of pro-inflammatory cytokines IL-6 and TNF-α. Meanwhile, owing to the multienzyme-like activities of mPB in nanoparticles, apoM@mPB@Ra NPs obviously alleviated cellular hypoxia, thereby decreasing the expression of VEGF. Notably, in a mouse model of DR, intravitreally injected apoM@mPB@Ra NPs significantly improved the severity of the abnormal retinal vascular network and inflammatory microenvironment of retinopathy by down-regulating the expression of HIF-1α, VEGF, and inflammatory-related cytokines. Collectively, these findings demonstrate that apoM@mPB@Ra NPs provide a promising and effective approach for the treatment of DR.
Insights
Apoptotic cell membrane-coated nanoparticles loaded with rapamycin show promise for treating diabetic retinopathy (DR). These nanoparticles modulate microglial polarization, reducing inflammation and improving retinal health in DR models.
Area of Science:
- Ophthalmology
- Nanomedicine
- Immunology
Background:
- Diabetic retinopathy (DR) is a leading cause of vision loss in diabetic patients.
- Microglia, the retinal immune cells, play a critical role in DR pathogenesis, contributing to inflammation, neovascularization, and neurodegeneration.
- Current treatments for DR often have limitations, necessitating the development of novel therapeutic strategies.
Purpose of the Study:
- To develop and evaluate novel immunomodulatory nanoparticles for ameliorating diabetic retinopathy (DR).
- To investigate the potential of apoptotic cell membrane-coated, rapamycin-loaded mesoporous Prussian blue nanoparticles (apoM@mPB@Ra NPs) in modulating microglial polarization for DR treatment.
Main Methods:
- Apoptotic retinal cell membrane-coated, rapamycin-loaded mesoporous Prussian blue nanoparticles (apoM@mPB@Ra NPs) were synthesized.
- The NPs were characterized for stability, biocompatibility, and targeted delivery capabilities.
- In vitro studies utilized an LPS-induced cellular inflammation model to assess microglial polarization, ROS scavenging, and cytokine expression.
- In vivo studies involved a mouse model of DR treated with intravitreal injection of apoM@mPB@Ra NPs to evaluate therapeutic efficacy.
Main Results:
- apoM@mPB@Ra NPs demonstrated favorable stability, biocompatibility, and targeted delivery to microglia.
- In vitro, NPs promoted M2 anti-inflammatory microglial polarization by scavenging ROS and affecting the mTOR pathway, downregulating IL-6 and TNF-α.
- NPs alleviated cellular hypoxia and reduced VEGF expression due to the multienzyme-like activities of mesoporous Prussian blue.
- In vivo, apoM@mPB@Ra NPs significantly improved retinal vascular network abnormalities and the inflammatory microenvironment in a mouse model of DR by downregulating HIF-1α, VEGF, and inflammatory cytokines.
Conclusions:
- apoM@mPB@Ra NPs effectively modulate microglial polarization towards an anti-inflammatory phenotype.
- These nanoparticles show significant therapeutic potential for treating diabetic retinopathy by reducing inflammation, hypoxia, and neovascularization.
- apoM@mPB@Ra NPs represent a promising nanomedicine-based approach for the treatment of diabetic retinopathy.
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