Carbon Nanodots-Integrated Multifunctional Nanomedicine Establishes a Regenerative Feedback Loop between Vascular-Immune-Muscle Systems for Comprehensive Therapy of Critical Limb Ischemia

Critical limb ischemia (CLI) remains a major clinical challenge, with high amputation and mortality rates. Dysregulated intercellular interactions among vascular, immune, and muscle systems in CLI undermine the body's repair processes. Herein, a multiactive nanomedicine, CDs@Zn@l-Arg, was developed by integrating <i>Panax notoginseng</i> saponin-derived carbon nanodots (CDs-PNS), zinc ions, and l-arginine to induce a mutually supportive cycle of angiogenesis, macrophage reprogramming, and muscle regeneration. CDs-PNS, first identified for their potent antioxidative, angiogenic, and macrophage-reprogramming properties in CLI therapy, are further enhanced by leveraging zeolitic imidazolate frameworks as mediators to physically encapsulate them, while l-arginine is incorporated through electrostatic binding and Schiff base reactions. Individual cell culture experiments demonstrate that, through the integration of various bioactive components, CDs@Zn@l-Arg effectively promotes endothelial tube formation and myosatellite cell proliferation and reduces inflammation and oxidative stress. More importantly, cell coculture models further reveal that CDs@Zn@l-Arg successfully reverses the detrimental intercellular interactions typical of CLI, thereby enhancing the positive crosstalk between endothelial cells, macrophages, and myosatellite cells. In a CLI mouse model, treatment with CDs@Zn@l-Arg significantly improves blood perfusion, reduces inflammation, and accelerates limb function recovery. Altogether, by establishing a regenerative feedback loop among the vascular-immune-muscle system, this multiactive nanomedicine holds promise for overcoming the multifaceted challenges of CLI, providing a breakthrough strategy for integrated therapy.