Abstract
Therapeutic angiogenesis is one of the most promising solutions to the clinical dilemma of critical limb ischemia (CLI). Promoting the morphogenesis of endothelial cells (ECs) and normalizing the microenvironment are the right pathways for angiogenesis, but existing strategies are limited by inefficiency, complexity and high cost. Oriented by clinical needs and engineering applications, an innovative nano-system was developed from bridging facile/cost-effective metal-organic frameworks (MOFs) for delivering bioactive zinc ion and versatile hydrogen sulfide (H2S). These MOFs were surface-modified with a multi-functional layer and evaluated as a potential tailored anti-hindlimb ischemic nanomedicine. As a holistic strategy, the combination of zinc ion and H2S generated from zinc MOFs (Zn-MOFs) and diallyl trisulfide (DATS) can integrally modulate EC behavior and microenvironment for more effective functional rehabilitation of ischemic limb. Specifically, zinc ion and H2S together amplified the pro-angiogenic effect on ECs, while H2S also alleviated post-ischemic oxidative stress and inflammation by inducing pro-healing and anti-inflammatory M2-type macrophages. Furthermore, surface-engineering of MOFs reduced the toxicity of nanomedicine and improved its utilization in intramuscular injection. Overall, the nano-system not only enables safe and effective H2S administration, but also presents a new potential option for CLI clinical therapy as an efficacious/facile/cost-effective nanomedicine.
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