Therapeutic strategies for critical limb ischemia: a focus on endogenous cell behavior modulation

Critical limb ischemia (CLI) represents the advanced stage of peripheral artery disease, with an extremely high rate of amputation and mortality. Conventional treatments, including surgical revascularization and percutaneous interventions, are constrained by invasiveness and unsuitability for certain patients, highlighting the urgent need for novel therapeutic approaches. Emerging strategies that regulate endogenous cell behavior offer an effective, less traumatic alternative with wider applicability. This review systematically summarizes therapeutic approaches focused on key cell populations-endothelial cells, macrophages, muscle satellite cells, and pericytes-integral to the pathogenesis and repair mechanisms of CLI. We focus on molecular interventions aimed at regulating growth factors, transcription factors, inflammatory mediators, and metabolic pathways to promote endothelial tube formation, macrophage reprogramming, muscle regeneration, and pericyte recruitment, ultimately enhancing collateral circulation, improving the microenvironment, and driving tissue repair. Additionally, we discuss the integration of advanced bioengineering approaches that leverage tools such as gene therapy, gasotransmitters, intelligent delivery systems, and functional biomaterials, which have significantly expanded the potential of CLI treatment. These engineered materials not only serve as carriers for targeted therapeutics but also actively modulate cellular behavior, providing sustained and localized intervention to optimize vascular repair and regeneration. Furthermore, the significance of intercellular crosstalk in the progression and treatment of CLI is emphasized, with great potential for synergistic enhancement of efficacy. By synthesizing the latest findings in CLI therapies based on cell behavior modulation, this review provides reference for innovative treatment paradigms and clinical applications.