Peptide-Based Hydrogels: Pep-1 and MMPS

Peptide Hydrogels as Innovative Biomaterials

Self-assembled peptide hydrogels have emerged as a new generation of revolutionary biomaterials due to their excellent biocompatibility, precisely designable structure and intelligent response to external stimuli. Among the many outstanding representatives, hydrogels constructed with the cysteine-rich self-assembling peptide Pep-1 (CGEMGWVRC) and responsive peptide fragments of matrix metalloproteinases (MMPs) are particularly noteworthy. Their unique physicochemical properties and biological functions provide promising platform solutions for tissue repair and regenerative medicine, precision drug delivery and other fields.

What Are Peptide Hydrogels?

Peptide hydrogels are three-dimensional structures with highly ordered nanofibrous networks formed by the self-assembly of short peptide or polypeptide molecules in water through non-covalent interactions (e.g., hydrogen bonding, hydrophobic interactions, π-π stacking, van der Waals forces, and specific covalent cross-links such as disulfide bonds). Such nanofiber networks can trap a large amount of water and form semi-solid materials with extracellular matrix-like (ECM) physical properties. Its core attraction lies in its "biophilicity" - good biocompatibility and biodegradability, which fundamentally avoids the risk of long-term inflammation or foreign body reaction that may be caused by traditional synthetic polymer materials. At the same time, the programmability of its amino acid sequence allows researchers to precisely regulate the hydrogel's mechanical strength, degradation rate, nano-topology, and even its behavior in response to specific biological signals (e.g., enzyme, pH, and temperature), thus realizing "on-demand customization" of the material's performance.

Advantages of Pep-1 and MMPS in Biomedical Applications

Pep-1 and MMPs-responsive peptide-based hydrogels have demonstrated irreplaceable advantages in the broad landscape of biomedical applications, with the core sequence of Pep-1, CGEMGWVRC, being the key to its functionality: the cysteine (C) residues at the ends provide stable cross-linking points and structural rigidity of the hydrogel through the formation of intramolecular or intermolecular disulfide bonds, while the hydrophilic/hydrophobic amino acid pattern (GEMGWVR) in the middle drives efficient intermolecular interactions and self-assembly of nanofibrils. mode (GEMGWVR) then drives efficient intermolecular interactions and nanofiber self-assembly. This structure endows Pep-1 hydrogels with desirable mechanical properties (e.g., tissue-like elastic modulus) and intrinsic bioactive potential. On the other hand, the design of responsive hydrogels for MMPs embodies the essence of "smart response". Matrix metalloproteinases (MMPs) are a class of zinc-dependent endopeptidases that are overexpressed during tissue remodeling (e.g., wound healing, embryonic development), inflammatory responses, and tumor invasion and metastasis. By using short peptide sequences (e.g., GPLG↓V RAG, IPES↓LR AG) recognized by specific MMPs (e.g., MMP-2, MMP-9) as cross-linking agents or integrating them into the hydrogel backbone, the constructed hydrogels are specifically cleaved by MMPs that are highly expressed at the site of the lesion. This feature enables MMPs-responsive hydrogels to achieve lesion-targeted drug release, on-demand degradation to support tissue regeneration, or intelligent activation of therapeutic pre-drugs in the tumor microenvironment, which greatly enhances the precision and efficiency of treatment.

Synthesis and Properties of Pep-1 and MMPS Hydrogels

Peptide-based hydrogels are usually prepared using a "bottom-up" self-assembly strategy, driven by precise control of environmental parameters (e.g., pH, ionic strength, temperature) or by triggering specific chemical reactions (e.g., oxidation to form disulfide bonds).

Self-Assembly Mechanism of Pep-1 (CGEMGWVRC)

Self-assembly of Pep-1 is the core process for its functional realization. The mechanism involves several key steps: under appropriate conditions (e.g., physiological pH or presence of mild oxidants), the cysteine residues at both ends of the peptide chain are oxidized to form a rigid intramolecular or intermolecular disulfide-bonded cyclized structure, which greatly limits the conformational freedom of the peptide chain and provides structural stability. At the same time, the indole ring of tryptophan (W) in the sequence generates strong hydrophobic interactions and π-π stacking with other aromatic or hydrophobic residues (e.g., methionine M, valine V). Glycine (G) and glutamic acid (E), on the other hand, provide the necessary flexibility and hydrophilicity. These synergistic intermolecular forces (disulfide bonding, hydrophobic interactions, hydrogen bonding) drive the Pep-1 molecules to align and elongate, resulting in nanofibers with high aspect ratios and diameters of about 10-20 nm. These nanofibers cross-link and entangle with each other to form a three-dimensional network structure throughout the system, encapsulating the water molecules to form a hydrogel with significant viscoelasticity. This sequence-determined, energy-minimizing self-assembly process gives Pep-1 hydrogels controlled rheological properties and desirable tissue-like mechanical properties.

MMPS Hydrogel Formation and Biocompatibility

The construction strategies of MMPs-responsive hydrogels are more diverse. Common approaches include: 1) directly using peptides containing MMPs enzymatic sites as the main structural units of hydrogels (e.g., self-assembled peptides) and using them to self-assemble to form a physical gel, with their enzymatic sites exposed in the network structure; 2) A "smart" hydrogel network can be formed by chemically cross-linking non-degradable polymer backbones, such as poly(ethylene glycol) (PEG), with matrix metalloproteinase (MMP)-cleavable peptide sequences. These peptide linkers serve as cross-linking agents and are covalently attached to the polymer chains. The key feature of this hydrogel is its responsiveness to specific MMPs. In environments rich in target MMPs—such as wound exudates or the tumor microenvironment—the peptide cross-links are selectively hydrolyzed. This enzymatic cleavage disrupts the hydrogel network by breaking the cross-linking points, resulting in structural changes such as hydrogel degradation, increased pore size, or the controlled release of encapsulated agents (e.g., drugs or cells). This response is highly specific and biologically relevant. In terms of biocompatibility, MMPs responsive hydrogels have the inherent advantages of peptide-based materials. Its constituent unit, amino acid, is the basic building block of living organisms, and the degradation products are usually non-toxic short peptides or amino acids, which can be naturally metabolized and absorbed by the organism. Through rational design of peptide sequences and strict control of the synthesis and purification process, these hydrogels exhibit extremely low cytotoxicity and good blood compatibility. In vitro cell culture experiments (e.g., using fibroblasts, endothelial cells or stem cells) typically show that cells adhere, spread, proliferate and maintain functional activity on the surface of the hydrogel or in the 3D-embedded state. In vivo implantation studies have also confirmed that it triggers a mild inflammatory response and good tissue integration. This excellent biocompatibility and degradability are the cornerstones of their successful application in in vivo biomedical scenarios.

Applications in Tissue Engineering and Controlled Drug Release

Peptide-based hydrogels, especially Pep-1 and MMPs-responsive hydrogels, show great translational potential in the fields of regenerative medicine and precision therapies due to their bionic ECM structures, tunable microenvironments, and smart responsiveness.

Using Peptide Hydrogels for Wound Healing

Pep-1 and MMPs-responsive hydrogels play a key role in the field of tissue engineering, especially in the treatment of chronic hard-to-heal wounds (e.g., diabetic ulcers, large burns). They can be used directly as 3D scaffold materials to mimic the physical and biochemical microenvironment of the natural ECM. On the one hand, their high water content and porous structure keep the wound moist and allow oxygen and nutrient exchange, while absorbing excess exudate and providing space for cell migration and proliferation. More importantly, Pep-1 hydrogel itself or its integrated functional peptides (e.g., RGD sequences) can actively promote the adhesion, migration, and proliferation of cells (fibroblasts, keratinocytes, endothelial cells), accelerating the process of granulation tissue formation and re-epithelialization, and the MMPs-responsive hydrogel achieves an intelligent coupling with the dynamics of wound healing: MMPs activity is significantly elevated in the wound during the inflammatory phase and the early stage of proliferation, and MMPs activity is significantly increased in the wound. During the inflammatory and early proliferative phases, MMPs activity is significantly elevated at the wound site and the hydrogel network is enzymatically degraded, releasing growth factors (e.g., VEGF, EGF, bFGF) or antimicrobial peptides loaded on the hydrogel to precisely stimulate neovascularization, cell proliferation, and infections on one hand, and on the other hand, the hydrogel is degraded in a timely manner to allow for the entry of new tissues and to avoid the physical obstruction that may be caused by the conventional materials. The study demonstrated that the bFGF-loaded MMPs-responsive hydrogel significantly accelerated the wound closure rate, improved the quality of neoplastic tissues and the degree of vascularization in a diabetic mouse wound model compared with a non-responsive control group, which demonstrated the advantages of its dynamic response to the wound microenvironment.

Smart Drug Delivery Systems Based on Peptide Hydrogels

In the field of controlled drug release, Pep-1 and MMPs-responsive hydrogels are ideal vehicles for localized, sustained, on-demand drug delivery platforms.Pep-1 hydrogels can be efficiently loaded with a variety of therapeutic molecules (small molecules of chemotherapeutic agents, proteins, nucleic acids, nanoparticles, etc.) by physical embedding or chemical bonding due to the nanofibrous network structure of Pep-1 hydrogels. Their relatively stable structure (especially when relying on disulfide bonds) provides sustained, diffusion-controlled drug release, which makes them particularly suitable for scenarios requiring long-term local drug delivery (e.g., post-operative anti-adhesion, anti-tumor topical therapy, local immunomodulation). MMPs-responsive hydrogels, on the other hand, elevate the "intelligence" of drug delivery to a new level, realizing precise release triggered by the disease microenvironment. In tumor therapy, chemotherapeutic agents (e.g., adriamycin, paclitaxel) or therapeutic nucleic acids are encapsulated in MMPs-responsive hydrogels, taking advantage of the generally high expression of MMPs (especially MMP-2 and MMP-9) in tumor tissues (especially invasive fronts and metastatic foci) and tumor-associated macrophages. After systemic or local injection, the gel remains stable in normal tissues to minimize off-target toxicity; once it reaches or is enriched in the tumor site with high expression of MMPs, the hydrogel network is specifically enzymatically cleaved to achieve burst or sustained targeted release of the drug, which can significantly increase the concentration and efficacy of the drug locally in the tumor, while at the same time reduce systemic toxicity and side effects. This responsive strategy based on key disease biomarkers has also been extended to the treatment of inflammatory diseases (e.g., arthritis) by releasing anti-inflammatory drugs in response to elevated MMPs in the synovial fluid of the diseased joints, demonstrating its great versatility and precise regulation.

Pep-1 (CGEMGWVRC) and MMPs responsive peptide hydrogels represent the cutting edge of biomaterial design. Its core strength lies in the integration of programmable molecular self-assembly, biomimetic physicochemical properties, and the ability to intelligently respond to key pathophysiological signals such as MMPs. From the in-depth analysis of Pep-1's nanofiber self-assembly mechanism based on disulfide bonding and hydrophobic interactions, to the clever design of MMPs overexpression for lesion-targeted degradation and drug-controlled release, these hydrogel systems provide a powerful and flexible platform tool for spanning the major challenges of tissue engineering and precision medicine. With the deepening understanding of peptide self-assembly mechanisms, the development of novel smart response sequences, and the combination of advanced manufacturing processes such as 3D bioprinting, peptide-based hydrogels will unleash even greater potential for advances in regenerative medicine and revolutionizing disease treatment paradigms.

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