Nanoparticle‐Driven Skeletal Muscle Repair and Regeneration Through Macrophage‐Muscle Stem Cell Interaction

Abstract Macrophages are key innate immune cells in the muscle environment of sarcopenia patients, significantly influencing muscle stem cell (MuSC) proliferation and differentiation. However, prolonged activation of macrophages can hinder muscle recovery. In this study, it synthesizes lipoic acid‐modified gold nanoparticles (LA‐Au NPs) of varying sizes to evaluate their biocompatibility and immunomodulatory effects. The findings demonstrate that LA‐Au NPs exhibit excellent biocompatibility with macrophages and promoted M2 polarization in a size‐dependent manner. Mechanistically, LA‐Au NPs facilitated metabolic reprogramming in macrophages by enhancing lysosomal autophagy and mitochondrial oxidative phosphorylation. Furthermore, macrophages are shown to chemotax toward MuSCs, regulating their proliferation via the chemokine system, inhibiting MuSC apoptosis, and enhancing differentiation under inflammatory conditions. In vivo studies have confirmed the safety and efficacy of LA‐Au NPs in sarcopenia mice. To further enhance the effectiveness of LA‐Au NPs, it investigates a delivery strategy that involves preconditioning macrophages with LA‐Au NPs (Mac@Au NPs). Compared to the direct injection of LA‐Au NPs, Mac@Au NPs demonstrate significantly greater benefits for muscle repair. This highlights the potential of macrophage therapy as a promising strategy for effective muscle regeneration and therapeutic intervention in sarcopenia.