Short-Peptide Biomaterials for Angiogenesis and Lymphangiogenesis: Advances in Tissue Engineering and Regenerative...

Vascular and lymphatic vessel regeneration is crucial for tissue repair and organ function restoration. However, conventional biomaterials are often constrained by poor biocompatibility and unpredictable degradation behavior. Engineered short peptides, typically comprising 2-50 amino acids, offer a promising solution for vessel regeneration through direct receptor engagement independent of exogenous cargo delivery. These peptides regulate cellular behavior through four key principles: sequence engineering, structural control, functional integration, and dynamic responsiveness. In angiogenesis, short-peptide biomaterials have demonstrated notable progress by enabling receptor-specific activation, multifunctional synergy, and the precise recognition of pathological microenvironments. Although studies on lymphatic regeneration remain limited, advances in identifying targeting sequences and mechanisms of lymphangiogenesis provide a foundation for peptide-based therapeutic strategies. Preclinically, short-peptide systems have shown therapeutic potential in cardiovascular, metabolic, and lymphatic disorders including acute myocardial infarction and diabetic complications. Furthermore, integration with artificial intelligence and 3D bioprinting is expanding the functional versatility of peptide-based biomaterials. Despite these advances, critical challenges remain, including limited predictability of sequence-structure-function relationships, stability-activity trade-offs in peptide modification, the underdevelopment of lymphangiogenic peptides, and barriers to scalable manufacturing and regulation. This review analyzes the biological basis of vascular and lymphatic regeneration, along with the design principles and mechanisms of short-peptide materials, systematically compares their regenerative strategies, highlights current limitations in bioactive peptide design and translation, and summarizes key advances and challenges to guide future development in this emerging field.