From revascularization to multimodal integrated therapy for peripheral arterial disease: immunomodulation, metabolic correction, and tissue engineering

Peripheral arterial disease (PAD), a critical manifestation of systemic atherosclerosis (AS), poses substantial therapeutic challenges. Despite pharmacological interventions and revascularization, efficacy remains constrained by high restenosis rates and suboptimal functional recovery. These limitations underscore a necessary transition from localized structural revascularization toward integrated systemic repair, with a particular focus on the underlying immunopathology. The progression of PAD is driven by a dysregulated immune response, characterized by an imbalance in macrophage polarization (M1/M2), overactivation of the NLRP3 inflammasome, and a vicious cycle of immune-metabolic coupling. Current research trajectories emphasize the synergistic orchestration of the vascular microenvironment through immunomodulation. Beyond modulating localized inflammatory responses, emerging strategies target metabolic homeostasis and advanced tissue engineering, including spatiotemporal growth factor delivery, extracellular vesicle-based therapies, and bioengineered scaffolding systems. These interdisciplinary developments point toward a multimodal integrated therapeutic strategy for PAD. Such a strategy would build on conventional revascularization and may address its limitations, including restenosis, through targeted immunomodulation and local tissue regeneration. Whether this approach can improve long-term outcomes compared with revascularization alone remains to be tested. If validated, it could shift the clinical standard beyond vessel patency toward comprehensive, long-term vascular health.