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Wound healing is a long‐term, multistage biological process that includes hemostasis, inflammation, proliferation, and tissue remodeling and requires intelligent designs to provide comprehensive and convenient treatment. The complexity of wounds has led to a lack of adequate wound treatment materials, which must systematically regulate unique wound microenvironments. Hydrogels have significant advantages in wound treatment due to their ability to provide spatiotemporal control over the wound healing process. Self‐assembling peptide‐based hydrogels are particularly attractive due to their innate biocompatibility and biodegradability along with additional advantages including ligand‐receptor recognition, stimulus‐responsive self‐assembly, and the ability to mimic the extracellular matrix. The ability of peptide‐based materials to self‐assemble in response to the physiological environment, resulting in functionalized microscopic structures, makes them conducive to wound treatment. This review introduces several self‐assembling peptide‐based systems with various advantages and emphasizes recent advances in self‐assembling peptide‐based hydrogels that allow for precise control during different stages of wound healing. Moreover, the development of multifunctional self‐assembling peptide‐based hydrogels that can regulate and remodel the wound immune microenvironment in wound therapy with spatiotemporal control has also been summarized. Overall, this review sheds light on the future clinical and practical applications of self‐assembling peptide‐based hydrogels. The main self‐assembling peptide‐based systems, the advantages of self‐assembling peptide‐based hydrogels, and the rational design of peptide‐based materials for different stages of wound healing are reviewed. Advanced self‐assembling peptide‐based materials that can be applied in spatiotemporally controllable, multifunctional wound healing and regulate/remodel the wound microenvironment are discussed. Prospects and challenges related to peptide‐based hydrogels for wound healing are also highlighted.

Designer self‐assembling peptides form the entangled nanofiber networks in hydrogels by ionic‐complementary self‐assembly. This type of hydrogel has realistic biological and physiochemical properties to serve as biomimetic extracellular matrix (ECM) for biomedical applications. The advantages and benefits are distinct from natural hydrogels and other synthetic or semisynthetic hydrogels. Designer peptides provide diverse alternatives of main building blocks to form various functional nanostructures. The entangled nanofiber networks permit essential compositional complexity and heterogeneity of engineering cell microenvironments in comparison with other hydrogels, which may reconstruct the tumor microenvironments (TMEs) in 3D cell cultures and tissue‐specific modeling in vitro. Either ovarian cancer progression or recurrence and relapse are involved in the multifaceted TMEs in addition to mesothelial cells, fibroblasts, endothelial cells, pericytes, immune cells, adipocytes, and the ECM. Based on the progress in common hydrogel products, this work focuses on the diverse designer self‐assembling peptide hydrogels for instructive cell constructs in tissue‐specific modeling and the precise oncology remodeling for ovarian cancer, which are issued by several research aspects in a 3D context. The advantages and significance of designer peptide hydrogels are discussed, and some common approaches and coming challenges are also addressed in current complex tumor diseases. Designer self‐assembling peptides are favorable building blocks compared to other hydrogels, which mimic 3D extracellular matrix at the nanometer scale by bioengineering nanotechnology. In 3D cell cultures, various cell constructs are fabricated by this kind of hydrogels in tissue engineering and regenerative medicine. Herein, the precise oncology remodeling is addressed by several main aspects involved in ovarian cancer.

Retinal ischemia is involved in the occurrence and development of various eye diseases, including glaucoma, diabetic retinopathy, and central retinal artery occlusion. To the best of our knowledge, few studies have reported self‐assembling peptide natural products for the suppression of ocular inflammation and oxidative stress. Herein, a self‐assembling peptide GFFYE is designed and synthesized, which can transform the non‐hydrophilicity of rhein into an amphiphilic sustained‐release therapeutic agent, and rhein‐based therapeutic nanofibers (abbreviated as Rh‐GFFYE) are constructed for the treatment of retinal ischemia‐reperfusion (RIR) injury. Rh‐GFFYE significantly ameliorates oxidative stress and inflammation in an in vitro oxygen‐glucose deprivation (OGD) model of retinal ischemia and a rat model of RIR injury. Rh‐GFFYE also significantly enhances retinal electrophysiological recovery and exhibits good biocompatibility. Importantly, Rh‐GFFYE also promotes the transition of M1‐type macrophages to the M2 type, ultimately altering the pro‐inflammatory microenvironment. Further investigation of the treatment mechanism indicates that Rh‐GFFYE activates the PI3K/AKT/mTOR signaling pathway to reduce oxidative stress and inhibits the NF‐κB and STAT3 signaling pathways to affect inflammation and macrophage polarization. In conclusion, the rhein‐loaded nanoplatform alleviates RIR injury by modulating the retinal microenvironment. The findings are expected to promote the clinical application of hydrophobic natural products in RIR injury‐associated eye diseases.

Ischemic diseases, especially in the heart and the brain, have become a serious threat to human health. Growth factor and cell therapy are emerging as promising therapeutic strategies; however, their retention and sustainable functions in the injured tissue are limited. Self-assembling peptide (SAP)-based hydrogels, mimicking the extracellular matrix, are therefore introduced to encapsulate and controllably release cells, cell-derived exosomes or growth factors, thus promoting angiogenesis and tissue recovery after ischemia. We will summarize the classification, composition and structure of SAPs, and the influencing factors for SAP gelation. Moreover, we will describe the functionalized SAPs, and the combinatorial therapy of cells, exosomes or growth factors with functionalized SAPs for angiogenic process as well as its advantage in immunogenicity and injectability. Finally, an outlook on future directions and challenges is provided.

AlphaFold, a deep learning–based platform widely used to predict protein and peptide structures, was employed in this study to model the self-assembling peptide RFC, which demonstrated a stable α-helical structure with high confidence. This structural prediction was supported by experimental analyses, which revealed the peptide’s ability to form dense fibrillar networks and robust hydrogels, particularly at higher concentrations. These hydrogels effectively supported the 3D culture of endometrial cancer organoids, which retained key tumor characteristics, including high proliferative activity and resistance to platinum-based drugs. Among tested therapeutics, Doxorubicin showed the strongest efficacy, significantly reducing organoid viability. This study highlights the predictive power of AlphaFold in elucidating peptide structures and guiding biomaterial development. The RFC hydrogel, combined with organoid modeling, represents a promising platform for advancing cancer research and precision medicine. These findings demonstrate the synergistic value of computational tools like AlphaFold and experimental approaches in creating innovative solutions for challenging biomedical applications.

Neurons have limited self‐repair ability, and typical treatment approaches for damaged tissue rely on surgery. Hindered by the lack of donor tissues and the complex neural environment, there is great interest in developing biomaterials to support neural regeneration. Self‐assembling peptides with fibrous structures mimicking the extracellular matrix have shown great potential as neurosupportive biomaterials. Previously, we identified peptide sequences derived from enhancing factor‐C (EF‐C) that are neurotrophic without additional supplements. Here, a library of nine EF‐C variants is designed by varying the hydrophobic core of the peptide backbone to elucidate its influence on self‐assembly and bioactivity. The physicochemical properties of these variants, including secondary structure and morphology, are thoroughly analyzed. Furthermore, molecular dynamics simulations based on AlphaFold 3 models are conducted, providing theoretical insights that explain the differential assembly and stability of EF‐C variants. Subsequently, the peptides are tested for bioactivity in a neuroblastoma cell line (SH‐SY5Y) to establish structure–property relationships. The structure‐forming EF‐C variants, particularly those featuring phenylalanine and isoleucine, are neurotrophic toward SH‐SY5Y cells, shown by enhanced ATP levels. The combination of experimental and computational methods provides a strategy for the accelerated design of neuro‐regenerative peptides. This study reports the design of neurosupportive peptide fibrils by systematically varying the hydrophobic core of EF‐C‐derived peptide variants. Peptides containing phenylalanine or isoleucine side chains are identified as having high aggregation propensities and performing superior in cell culture studies. The combination of biophysical assays with computational modeling and simulation can accelerate the design of self‐assembling peptide biomaterials.

Regenerative medicine is a complex discipline that is becoming a hot research topic. Skin, bone, and nerve regeneration dominate current treatments in regenerative medicine. A new type of drug is urgently needed for their treatment due to their high vulnerability to damage and weak self-repairing ability. A self-assembled peptide hydrogel is a good scaffolding material in regenerative medicine because it is similar to the cytoplasmic matrix environment; it promotes cell adhesion, migration, proliferation, and division; and its degradation products are natural and harmless proteins. However, fewer studies have examined the specific mechanisms of self-assembled peptide hydrogels in promoting tissue regeneration. This review summarizes the applications and mechanisms of self-assembled short peptide and peptide hydrogels in skin, bone, and neural healing to improve their applications in tissue healing and regeneration.

Current therapies for the devastating damage caused by traumatic brain injuries (TBI) are limited. This is in part due to poor drug efficacy to modulate neuroinflammation, angiogenesis and/or promoting neuroprotection and is the combined result of challenges in getting drugs across the blood brain barrier, in a targeted approach. The negative impact of the injured extracellular matrix (ECM) has been identified as a factor in restricting post‐injury plasticity of residual neurons and is shown to reduce the functional integration of grafted cells. Therefore, new strategies are needed to manipulate the extracellular environment at the subacute phase to enhance brain regeneration. In this review, potential strategies are to be discussed for the treatment of TBI by using self‐assembling peptide (SAP) hydrogels, fabricated via the rational design of supramolecular peptide scaffolds, as an artificial ECM which under the appropriate conditions yields a supramolecular hydrogel. Sequence selection of the peptides allows the tuning of these hydrogels' physical and biochemical properties such as charge, hydrophobicity, cell adhesiveness, stiffness, factor presentation, degradation profile and responsiveness to (external) stimuli. This review aims to facilitate the development of more intelligent biomaterials in the future to satisfy the parameters, requirements, and opportunities for the effective treatment of TBI. Modulating the physicochemical properties of self‐assembled peptide (SAP) hydrogels such as charge, hydrophobicity/hydrophilicity, cell adhesiveness, stiffness, therapeutic/growth factor presentation, and responsiveness to (external) stimuli can reduce neuroinflammatory responses and enhance neuroprotection in the treatment of traumatic brain injury.

Objectives This study evaluated the adhesion and whitening effects of a combination of P11-4 self-assembling peptide and hydroxyapatite (peptide-HAP) on bovine enamel. Methods Forty-six caries-free bovine teeth were selected, and 40 teeth were randomly allocated to one of five groups ( n = 8). First, the effects of application frequency, exposure time, and storage in saliva on the whitening effects of an experimental low-concentrated peptide-HAP suspension (0.5 wt% HAP; Curodont, Credentis) were evaluated and compared with a commercial bleaching agent (VivaStyle Paint on Plus, VS, Ivoclar Vivadent). Tooth color was measured using a spectrophotometer (Gretag MacBeth), and color changes ΔE were statistically analyzed. Second, the effects of peptide-HAP concentration (low versus high: 6.25% HAP; Curodont Protect), and its interactions with saliva and postapplication restaining, were investigated. Third, enamel surfaces ( n = 2) were treated with low concentration peptide-HAP and high-concentration peptide-HAP in polymeric and monomeric forms (Curodont Protect & Curodont Repair, Credentis) and analyzed by SEM. Results The Δ E of the low-concentration peptide-HAP suspension did not differ from that of VS. Application frequency, exposure time, and storage in saliva did not have any significant impact on whitening efficacy of the peptide-HAP suspension. Increasing the concentration of the suspension did not promote overall Δ E . SEM observations confirmed the presence of the newly generated peptide and HAP on the enamel surface. Conclusions The peptide-HAP suspension is a mild tooth whitener, and the adhesion of peptide-HAP to enamel is concentration dependent. Clinical relevance This peptide-HAP suspension is effective in offsetting discoloration caused by restaining after treatment.

Background Self‐assembling peptides (TDMs) comprise synthetic amphipathic peptides that immediately react to changes in pH and/or inorganic salts to transform into a gelatinous state. The first generation of these peptides (TDM‐621) is currently used as a hemostatic agent in Europe. However, TDM‐621 exhibits slow gel‐formation and low retention capabilities on tissue surfaces. The second generation (TDM‐623) was therefore developed to encourage faster gel‐formation and better tissue‐sealing capabilities. Aim The aim of this study was to verify the efficacy of TDM‐623 in terms of its hemostatic effect in endoscopic surgery. Materials and methods Evaluation of the hemostatic effect in endoscopic surgery (animal study) was performed using eight porcine in spine position. Following systemic heparinization, we established a “bleeding model” by endoscopic grasping forceps on the anterior walls of the stomach and duodenum. In the hemostasis method, an endoscope with a distal hood was brought into contact with the bleeding point, and 1 ml TDM‐623 was applied to the wound. After TDM‐623 gelation, the endoscope was removed, and the acute hemostatic effect (after 2 min) was confirmed. Result In the endoscopic bleeding model, 17 of the 23 cases (74%) showed complete hemostatic effects on the anterior wall of the stomach, and 18 of the 20 cases (80%) on the anterior wall of the duodenum, respectively. None of the applied gels were displaced from the anterior walls of the stomach and duodenum. Conclusion The new self‐assembling peptide (TDM‐623) showed high hemostatic effects. TDM‐623 had potential usefulness for upper gastrointestinal endoscopic surgery.