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M3-DPPE Liposomal Nanoparticles Encapsulating CLEC12A Enhance CD206-Mediated Endocytosis and Efficacy in the
Shulin Luo1, Junfeng Cai1, Feng Yin1
1Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
Objective:
This study aimed to investigate the efficacy of M3-DPPE liposomal nanoparticles encapsulated with mRNA encoding cytokines (M3-mRNAs) in targeting macrophages for the treatment of inflammation-induced joint injury.
Methods:
in vitro, M3-mRNAs were administered to peritoneal exudate macrophages (PEMs), and the uptake was assessed using flow cytometry. The mechanism of uptake was investigated by blocking the CLEC12A pathway with M3-SiCLEC12A and observing CD206-mediated endocytosis. In vivo, the distribution of Dir-labeled M3-drugs was monitored using IVIS imaging, and its accumulation in inflammatory and noninflammatory areas was evaluated. The therapeutic potential was evaluated in collagen-induced arthritis (CIA) model mice by assessing macrophage polarization, joint pathology, and cytokine expression.
Results:
in vitro studies demonstrated that M3-mRNAs were taken up significantly by PEMs via CD206-mediated endocytosis. In vivo imaging showed that Dir-labeled M3-drugs accumulated predominantly in inflammatory areas and subsequently in bone injury joints. Treatment with M3-drugs in collagen-induced arthritis model mice increased the population of F4/80+ and F4/80+/CD206+ M2 macrophages in inflamed joints, leading to reduced joint fibrosis and modulation of cytokine levels, including decreased pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, and INF-γ) and increased anti-inflammatory cytokines (IL-10 and TGF-β).
Conclusions:
M3-SiCLEC12A enhanced CD206-mediated endocytosis of M3-mRNAs and M3-drugs in macrophages, promoting the production of corresponding proteins and modulating the immune microenvironment. This treatment approach shows promise in repairing inflammation-induced bone and joint injury by balancing pro-inflammatory and anti-inflammatory cytokines. However, further research is required to address drug tolerance and safety concerns and minimize potential side effects before clinical application in autoimmune diseases caused by inflammation.
Insights
Liposomal nanoparticles carrying mRNA effectively target macrophages to treat joint injuries. This approach reduces inflammation and promotes healing by rebalancing immune responses, showing promise for future therapies.
Area of Science:
- Biomedical Engineering
- Immunology
- Nanomedicine
Background:
- Inflammation-induced joint injuries pose significant therapeutic challenges.
- Targeting macrophages is a key strategy for modulating the immune response in joint diseases.
- Developing effective drug delivery systems for localized treatment is crucial.
Purpose of the Study:
- To investigate the efficacy of M3-DPPE liposomal nanoparticles carrying mRNA encoding cytokines (M3-mRNAs) for treating inflammation-induced joint injury.
- To evaluate the targeted delivery of M3-mRNAs to macrophages.
- To assess the therapeutic potential in a collagen-induced arthritis (CIA) mouse model.
Main Methods:
- In vitro studies using peritoneal exudate macrophages (PEMs) to assess mRNA uptake via flow cytometry.
- Investigating the uptake mechanism using pathway blocking agents (M3-SiCLEC12A) and assessing CD206-mediated endocytosis.
- In vivo tracking of labeled nanoparticles using IVIS imaging and evaluating accumulation in inflammatory sites.
- Assessing therapeutic effects in CIA mice, including macrophage polarization, joint pathology, and cytokine expression analysis.
Main Results:
- M3-mRNAs demonstrated significant uptake by PEMs through CD206-mediated endocytosis in vitro.
- In vivo imaging confirmed preferential accumulation of M3-drugs in inflammatory areas and injured joints.
- Treatment in CIA mice increased M2 macrophage populations, reduced joint fibrosis, and modulated cytokine profiles, decreasing pro-inflammatory and increasing anti-inflammatory cytokines.
Conclusions:
- M3-SiCLEC12A enhances macrophage uptake of M3-mRNAs and M3-drugs, promoting protein production and immune microenvironment modulation.
- This nanoparticle-based approach holds promise for repairing inflammation-induced bone and joint injuries by balancing immune responses.
- Further research is needed to address drug tolerance, safety, and potential side effects for clinical application in inflammatory autoimmune diseases.
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