Design Strategies for Advanced Biomaterials Functionalized with Bioactive Peptides

A vast library of bioactive peptides provides a versatile toolkit for engineering biological functionality into materials. This peptide repertoire encompasses a broad range of bioactivities, including cell adhesion, protease lability, signaling activation, and immunomodulation. As a result, these peptides have been widely used in biomaterial design to instruct cell behavior and control biological outcomes. Given the complexity and highly dynamic nature of native cellular microenvironments, emerging approaches focus on developing multifunctional and stimuli-responsive biomaterials that better recapitulate these biological systems. Designing such materials requires integrating biochemical mechanisms that drive specific cellular responses while optimizing material properties to enhance desired functionality. In this review, we describe emerging design strategies and key considerations for peptide-functionalized materials, with an emphasis on the molecular interactions and biochemical mechanisms that inform their design. We discuss how synergistic cues, peptide structural conformation, and modes of motif presentation are used to regulate cell-material interactions and downstream signaling. We also highlight molecular- and material-based strategies to impart endogenous and exogenous stimulus-responsive behavior, as well as the influence of intrinsic material properties on peptide bioactivity. Advances in computational and data-driven approaches for the discovery and optimization of de novo bioactive peptides and biomaterials, coupled with new insights into biological mechanisms and protein structures, are accelerating the design of materials that more closely recapitulate natural environments for diverse biomedical applications.