Fundamentals and Advances in Programmable Peptide Hydrogels for Multifunctional Biomedical Applications: A Review.

Programmable peptide hydrogels represent advanced supramolecular biomaterials featured with customizable molecular sequences and tunable self-assembly behaviors, which can biomimetically reconstruct the structural and microenvironmental complexity of native extracellular matrix. This review systematically elaborates the molecular engineering advances of programmable peptide hydrogels following a hierarchical logic from fundamental mechanisms to translational applications. We first interpret the intrinsic self-assembly mechanisms driven by non-covalent interactions and the regulatory effects of typical external microenvironmental stimuli. On this basis, we summarize core rational design principles, covering stimuli-responsive structural optimization, biofunctional modification, and the tunable regulation of physical properties, degradability and immunogenicity. Furthermore, we correlate multi-scale structural features (nanostructures, porous architecture and mechanical properties) with their versatile biomedical functions, and comprehensively discuss their cutting-edge applications in tissue regeneration, targeted drug and gene delivery, cell-mediated therapy, immunomodulation, and anti-infective treatment. Finally, we identify critical translational barriers including batch-to-batch inconsistency, immunogenic risks, and in vivo performance instability, and highlight future directions involving multi-stimuli-responsive systems, artificial intelligence-assisted design, computational modeling, and hybrid material construction. This work systematically clarifies the structure-property-function relationship of peptide hydrogels, and underscores their great potential as next-generation platforms for precision regenerative medicine and targeted disease intervention.