Mechanism-Guided Nanoengineered Therapeutic Peptides for Bone Healing.

Bone healing is frequently compromised not by the absence of a single osteogenic factor, but by the breakdown of coordinated biological processes, including inflammatory resolution, vascular invasion, endogenous cell recruitment, matrix mineralization, and remodeling. Therapeutic peptides are attractive for bone repair because they are chemically defined, modular, and readily engineered to encode diverse functions such as immunomodulation, angiogenic activation, osteogenic signaling, antimicrobial activity, and mineral binding. However, in their free or conventionally delivered forms, peptides often suffer from rapid degradation, diffusion, burst release, poor local retention, and inadequate spatiotemporal presentation, limiting their efficacy in complex defects. Nanoengineering provides the missing level of control by converting sequence-defined peptides into retained, clustered, responsive, and matrix-integrated nanoscale signals that can be interpreted by cells within the evolving defect niche. Unlike previous reviews that are typically organized by material platform (eg, hydrogels, scaffolds) or by peptide category (eg, biomimetic, antimicrobial), this Review adopts a mechanism-guided framework that is structured around the sequential biological bottlenecks of bone healing-from inflammatory resolution and vascular invasion to mineralization and remodeling-and critically examines how nanoengineering transforms peptide sequence information into spatiotemporally effective signals at each stage. It first discusses how sequence features encode regenerative potential and how nanoscale presentation determines whether that potential becomes biologically effective. The field is then organized according to the major biological bottlenecks that peptide nanoengineering can overcome, including immuno-osteogenesis, angiogenic-osteogenic coupling, mineralization guidance, and endogenous cell recruitment. Problem-oriented applications in compromised healing are further examined, with emphasis on infected bone defects and osteoporotic bone repair, and it is argued that biomaterialization acts as a mechanism-amplifying extension of peptide nanoengineering by adding four critical functions: retention, geometry, responsiveness, and defect-specific context matching. Finally, emerging opportunities in AI-assisted peptide design, stage-matched delivery, mineralization-guiding nanoarchitectures, and translational validation in load-bearing and nonunion-relevant models are highlighted. Together, this Review positions nanoengineered therapeutic peptides as a promising preclinical platform that may advance toward more targeted and mechanism-informed strategies for bone regeneration.