A recent study published in Small reports on the synthesis and evaluation of lipoic acid-modified gold nanoparticles (LA-Au NPs) of varying sizes, with a focus on their biocompatibility and immunomodulatory effects on macrophages.
Muscle regeneration, particularly in injury or disease contexts, is highly dependent on the function of muscle stem cells (MuSCs) and their interaction with macrophages. This work investigates the potential of LA-Au NPs to promote M2 polarization in macrophages and thereby support MuSC activation and muscle repair.
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Background
Sarcopenia, defined by progressive loss of muscle mass and function, is a growing clinical concern in aging populations. Dysregulation of the muscle microenvironment—especially the balance between MuSC activity and immune cell signaling—is a key factor in impaired regeneration.
Macrophages are central to this process, capable of shifting between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, with the latter associated with tissue repair. Therapeutic strategies that support the transition from M1 to M2 macrophages may improve regenerative outcomes.
Nanoparticles, particularly gold-based nanomaterials, have gained attention for their ability to modulate immune responses while offering high biocompatibility and tunable surface properties. Lipoic acid, a bioactive compound with antioxidant properties, was used to modify gold nanoparticles to enhance their therapeutic interaction with immune cells involved in muscle repair.
Study Design
The researchers synthesized LA-Au NPs via ligand exchange, starting with citric acid-stabilized gold nanoparticles, followed by functionalization with lipoic acid. Nanoparticles of different sizes were characterized and evaluated for their effects on macrophage function and metabolism.
Macrophages preconditioned with LA-Au NPs—called Mac@Au NPs—were studied in vitro using Raw 264.7 cells to assess M2 polarization. Co-culture experiments were also conducted to evaluate their influence on MuSC activation under oxidative stress.
In vivo validation was performed using a glycerol-induced sarcopenia mouse model, with treatment groups receiving either LA-Au NPs or Mac@Au NPs. Muscle regeneration was assessed through metrics such as tissue mass, functional performance, and molecular indicators of repair.
Results and Analysis
LA-Au NPs promoted M2 polarization in a size-dependent manner, with distinct nanoparticle sizes exerting different degrees of influence on macrophage phenotype. Treated macrophages displayed enhanced lysosomal autophagy and mitochondrial function—key metabolic processes associated with reparative activity.
Co-culture studies showed that MuSCs exposed to LA-Au NP-conditioned macrophages exhibited improved activation, proliferation, and differentiation, particularly under stress conditions mimicking a degenerative muscle environment.
In vivo, Mac@Au NP treatment improved muscle mass and strength, and also enhanced motor coordination and endurance in the sarcopenia model. These outcomes were accompanied by increased vascularization, as indicated by elevated Vascular Endothelial Growth Factor (VEGF) expression from treated macrophages.
Importantly, the preconditioning strategy—using macrophages as carriers for LA-Au NPs—demonstrated superior regenerative outcomes compared to direct nanoparticle administration, suggesting a functional advantage in using immune cells as delivery and modulation vehicles.
Toxicological assessments indicated no significant adverse effects in major organs, supporting the biocompatibility of the nanoparticles under the study conditions.
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Conclusion
This study highlights the potential of lipoic acid-modified gold nanoparticles as immunomodulatory agents for muscle repair. By promoting M2 macrophage polarization and supporting MuSC function, LA-Au NPs offer a targeted approach for addressing impaired regeneration associated with sarcopenia.
The macrophage preconditioning strategy (Mac@Au NPs) demonstrated enhanced therapeutic efficacy in vivo, presenting a viable pathway for nanomedicine-based interventions in muscle degenerative conditions.
Further research is warranted to refine delivery mechanisms, optimize nanoparticle size and dosing, and evaluate long-term safety. Nonetheless, these findings contribute to the growing body of work exploring immune-nanoparticle interactions as a means to modulate tissue repair processes in aging and disease contexts.
Journal Reference
Xu L., et al. (2025). Nanoparticle‐Driven Skeletal Muscle Repair and Regeneration Through Macrophage-Muscle Stem Cell Interaction. Small 2412611. DOI: 10.1002/smll.202412611, https://onlinelibrary.wiley.com/doi/10.1002/smll.202412611