Research Progress and Translational Prospects of Peptide-Composite Biomaterials in Promoting Peripheral Nerve Injury Repair

Peripheral nerve injury, caused by various factors such as trauma, surgery, and disease, often leads to sensory abnormalities, muscle weakness, and even permanent loss of motor function, representing a prevalent and challenging clinical condition. Autologous nerve grafting, the current "gold standard" for repair, suffers from inherent limitations including limited donor source, donor-site morbidity, and nerve size mismatch. While artificial nerve conduits serve as alternatives, they often fail to achieve long-distance, high-precision nerve regeneration due to a lack of bioactive signaling. Peptide-composite biomaterials, leveraging the advantages of small-molecule peptides—such as high specificity, low immunogenicity, and ease of modification—seamlessly integrate bioactive signals with biomaterial scaffolds. They can precisely regulate the behavior of neurons, Schwann cells, immune cells, and endothelial cells, synergistically promoting nerve repair through four core processes: axon growth, cellular support, inflammatory microenvironment remodeling, and angiogenesis. This provides a novel pathway to overcome the clinical bottleneck in peripheral nerve injury repair. This article will systematically outline the design logic and mechanisms of action of peptide-composite biomaterials, elucidate the molecular mechanisms by which active peptides regulate nerve regeneration, comprehensively summarize the application paradigms of various functional peptides in nerve repair, objectively analyze the core challenges in current clinical translation, and prospectively envision future development directions in this field, offering comprehensive theoretical support and practical guidance for biomaterial-based repair strategies for peripheral nerve injury.

1.Core Requirements for Peripheral Nerve Regeneration and the Core Value of Peptide-Composite Biomaterials

Peripheral nerve regeneration is a complex process involving multiple cells, stages, and coordinated signals. Injured nerves not only require a physical scaffold to bridge the defect but also need precise biological signal modulation to accomplish axon extension, myelin regeneration, inflammation resolution, and vascular reconstruction. Traditional biomaterials can only provide physical support and fail to mimic the native microenvironment for nerve regeneration. Meanwhile, full-length protein factors face issues like poor stability, high immunogenicity, and high cost, limiting their clinical application. Peptide-composite biomaterials utilize synthetically functional peptides as the active core, incorporating them into biomaterial scaffolds such as hydrogels, nanofibers, and conduits via covalent grafting, physical loading, or self-assembly. This approach retains the mechanical support and structural compatibility of the scaffold while enabling the sustained release of precise biological signals. This article will emphasize that such materials can simulate extracellular matrix functions, activate neurotrophic pathways, regulate immune polarization, and promote angiogenesis, perfectly matching the full-cycle needs of peripheral nerve regeneration. Simultaneously, they circumvent the drawbacks associated with protein-based factors, emerging as a new nerve repair solution that combines safety and efficacy.

2.Four Core Mechanisms by Which Peptide-Composite Biomaterials Regulate Nerve Regeneration

2.1 Driving Efficient Axon Extension, Opening the Main Pathway for Nerve Regeneration

Axon extension is the core of nerve repair. Peptide-composite biomaterials employ multiple strategies to overcome obstacles to axon growth: First, mimicking neurotrophic factor functions to activate receptors like TrkA/TrkB, initiating downstream pathways such as PI3K-Akt and ERK1/2, thereby providing survival and growth signals for neurons. Second, simulating cell-cell and cell-matrix adhesion by enhancing axon-scaffold adhesion via integrin-binding motifs, guiding directional axon growth. Third, inhibiting endogenous inhibitory pathways like RhoA/ROCK, releasing the collapse of growth cones, and continuously propelling axon advancement. Fourth, achieving targeted delivery to neurons, improving the efficiency of active substances, and preventing signal wastage.

2.2 Enhancing Schwann Cell Function, Building a Support Network for Nerve Regeneration

Schwann cells are the central support cells for peripheral nerve regeneration. Peptide-composite biomaterials can precisely regulate their phenotype and behavior: On one hand, inducing Schwann cell reprogramming towards a repair phenotype, upregulating key transcription factors like c-Jun, and promoting the secretion of neurotrophic factors and the expression of myelin-related genes. On the other hand, guiding the directional migration of Schwann cells to form Büngner bands, creating physical guides for axon growth, while accelerating myelin regeneration to restore nerve signal conduction.

2.3 Remodeling the Inflammatory Microenvironment, Creating a Permissive Environment for Nerve Regeneration

The inflammatory response post-nerve injury is a double-edged sword; excessive inflammation exacerbates tissue damage, while appropriate inflammation clears debris and initiates repair. This article will clarify that peptide-composite biomaterials can bidirectionally regulate the inflammatory process: In the early stage, they accelerate the pro-inflammatory phase, promoting macrophages and neutrophils to clear myelin debris and necrotic tissue. In the mid-to-late stages, they drive macrophage polarization towards the M2 phenotype, upregulate the release of anti-inflammatory factors, inhibit chronic inflammatory damage, reduce neuropathic pain and tissue fibrosis, thereby creating a stable, permissive microenvironment for nerve regeneration.

2.4 Promoting Vascularization in the Injury Zone, Ensuring Nutritional Supply for Nerve Regeneration

Angiogenesis is the material basis for nerve regeneration, as sufficient blood supply provides oxygen and nutrients to repairing cells. Peptide-composite biomaterials can mimic the functions of pro-angiogenic factors like VEGF and FGF, activating the proliferation, migration, and lumen formation of endothelial cells. This rapidly reconstructs the vascular network in the injured area. Concurrently, they synergize with nerve regeneration signals to achieve synchronized vascular and neural repair, preventing regeneration failure due to nutritional deficiencies.

3.Classification of Functional Peptides and Their Applications in Nerve Repair

3.1 Neurotrophic Mimetic Peptides

These peptides mimic the core functional sequences of neurotrophic factors like BDNF and NGF. They can activate neuroprotective and axon growth pathways without requiring the full-length protein, offering greater stability and no immune risk. They efficiently promote neuronal survival and axon extension, making them the most widely researched type of functional peptide.

3.2 Cell Adhesion and Targeting Peptides

Adhesion peptides derived from laminin and fibronectin enhance cell-material binding. Neuron-targeting peptides specifically recognize receptors on neural cell surfaces, enabling precise delivery of active signals, improving repair efficiency, and reducing non-specific effects.

3.3 Anti-inflammatory and Immune-Modulatory Peptides

By blocking pro-inflammatory pathways like JAK-STAT and TNF-α, or activating tissue repair receptors, these peptides regulate immune cell polarization. They accelerate the clearance of injury debris while preventing excessive inflammation, simultaneously alleviating neuropathic pain, thereby achieving a dynamic balance between inflammation and regeneration.

3.4 Pro-angiogenic Peptides

Mimicking the active sequences of vascular growth factors, these peptides induce angiogenesis with low cost and high stability, addressing the issue of insufficient blood supply in nerve repair zones. Combined with nerve regeneration peptides, they can achieve synergistic effects.

3.5 Multifunctional and Synergistic Peptides

A single peptide can possess multiple functions, or multiple peptides can be combined within a single scaffold to simultaneously achieve neurotrophic, cell-adhesive, anti-inflammatory, and pro-angiogenic effects. This matches the complex requirements of nerve regeneration and represents a core direction for future functional peptide design.

4.Core Challenges in the Clinical Translation of Peptide-Composite Biomaterials

Current practical bottlenecks hindering the transition of peptide-composite biomaterials from the laboratory to the clinic include:

First, challenges in controlling peptide activity and stability: Material grafting methods can easily alter peptide conformation, leading to reduced activity, and achieving precise control over sustained release and duration of action in vivo is difficult. Second, insufficient precision in regeneration: Current strategies mostly focus on increasing the number of nerve fibers, failing to achieve precise targeted regeneration of motor, sensory, and autonomic nerves, which can easily lead to nerve mismatch. Third, limitations of preclinical models: Most studies are based on rat models with small gap defects, which have significant physiological differences from long-distance, complex injuries in humans, making experimental results hard to translate. Fourth, manufacturing process and industrialization constraints: The synthesis of multifunctional peptides and precise grafting processes are complex, with poor batch-to-batch consistency and high costs. Furthermore, unified quality evaluation standards are lacking. Fifth, long-term safety requires verification: The biocompatibility of peptide metabolites and material degradation products in vivo still needs validation through long-term large-animal experiments.

5.Future Development Directions for Peptide-Composite Biomaterials

First, intelligent and responsive design: Developing intelligent release systems responsive to pH and enzyme concentrations in the injury microenvironment to achieve timed and targeted peptide release, matching the spatiotemporal patterns of nerve regeneration. Second, multimodal functional integration: Combining physical signals (conductive, piezoelectric, photothermal) with biopeptide signals to construct multimodal synergistic repair scaffolds, further enhancing regeneration efficiency. Third, personalized customization strategies: Customizing compatible peptide-composite scaffolds based on patient injury type, length, and location to achieve precise, individualized repair. Fourth, breakthroughs in industrialization technology: Optimizing peptide synthesis and material grafting processes to reduce production costs, establishing unified quality control and evaluation systems to promote product realization. Fifth, interdisciplinary innovation: Combining AI algorithms to design highly active peptide sequences, integrating 3D printing to construct biomimetic nerve scaffolds, achieving full-chain optimization from molecular design to macrostructure.

6.Summary

Peptide-composite biomaterials overcome the functional limitations of traditional nerve repair materials. Using small-molecule active peptides as core signaling molecules, they comprehensively empower peripheral nerve regeneration from four dimensions: axon growth, cellular support, inflammation regulation, and angiogenesis. Combining safety, efficacy, and customizability, they represent an ideal alternative to autologous nerve grafting. This article has comprehensively outlined the design principles, mechanisms of action, application status, translational challenges, and future directions in this field, clearly demonstrating the core value and development potential of peptide-composite biomaterials in peripheral nerve injury repair. It provides a systematic and complete reference framework to advance both fundamental research and clinical translation in this area, facilitating a leap forward for peripheral nerve injury repair technology from foundational research to clinical application.

Original Article：

Zhao, Zhiwei, et al. "Peptide‐Incorporated Biomaterials Promote Regeneration of Peripheral Nerve Injuries." Advanced Science (2026): e24264.