Peptide metabolites are emerging biomolecules with numerous possibilities in biomaterial-based regenerative medicine due to their inherent bioactivities. These small, naturally occurring compounds are intermediates or byproducts of larger proteins and peptides, and they can have profound effects, such as antiviral therapeutics, proangiogenic agents, and regenerative medicinal applications. This study is among the first to focus on using thymosin β4 protein-derived metabolites to pioneer novel applications for peptide metabolites in biomaterials. This study found that the novel peptide metabolite acetyl-thymosin β4 (amino acid 1–17) (Ac-Tβ_1-17) exhibited significant protease inhibition activity against SARS-CoV-2, surpassing its precursor protein. Additionally, Ac-Tβ_1-17 demonstrated beneficial effects, such as cell proliferation, wound healing, and scavenging of reactive oxygen species (ROS) in human umbilical vein endothelial cells (HUVEC). Integrating Ac-Tβ_1-17 into a peptide-based scaffold facilitated cell growth and angiogenesis inside the scaffold and through gradual release into the surrounding environment. The Ac-Tβ_1-17 peptide treatment induced significant biochemical responses in HUVEC, increasing Akt, ERK, PI3K, MEK, and Bcl-2 gene expression and proangiogenic proteins. Ac-Tβ_1-17 peptide treatment showed similar results in ex vivo by enhancing mouse fetal metatarsal growth and angiogenesis. These findings highlight the potential of natural protein metabolites to generate biologically active peptides, offering a novel strategy for enhancing biomaterial compatibility. This approach holds promise for developing therapeutic biomaterials using peptide metabolites, presenting exciting prospects for future research and applications.

The therapeutic application of peptides has expanded considerably in clinical and regenerative medicine; however, the contribution of peptide metabolites to therapeutic efficacy remains poorly understood. We previously identified N -acetyl- l -leucyl- l -lysine (Ac-LK) as the major metabolite of TB-500 by metabolic profiling and hypothesized that it contributes to the biological activity of the parent peptide. Initial screening demonstrated that Ac-LK exhibited greater SARS-CoV-2 main protease inhibitory activity than TB-500, the other identified metabolites, and the constituent amino acids. We therefore systematically characterized Ac-LK using cellular uptake, endothelial cell functional assays, proteomic profiling, and in vivo wound healing. Under the experimental conditions employed, Ac-LK exhibited enhanced protection against hypoxia/reoxygenation-induced injury, stronger promigratory and barrier-stabilizing activities, broader regulation of pathways related to cytoskeletal organization, cadherin-mediated adhesion, and protein translation, and accelerated wound healing. Collectively, these findings identify Ac-LK as a biologically active metabolite of TB-500 and support the hypothesis that metabolic conversion contributes to the therapeutic actions of the parent peptide.

Burn injuries cause deep, extensive skin damage and are associated with high morbidity and mortality. Effective treatment goes beyond superficial wound coverage; it requires regenerative repair that progresses from deeper tissue layers to complete skin restoration. Because of extreme trauma and severity, the fastest treatment strategies play a key role in the treatment of burn injuries. Recently, hydrogel dressings have gained attention as promising wound care options because they maintain a moist environment, provide cooling and pain relief, support autolysis, and promote tissue regeneration. However, the lack of biological function and, consequently, slower tissue regeneration limit the applications of hydrogels. In recent years, collaboration between doctors, materials scientists, and biologists has substantially improved the biological functionality of hydrogels. Integrating bioactive agents, such as proteins, peptides, antimicrobial compounds, drugs, metal nanoparticles, cell-based vesicles, and extracellular matrix, enables the development of multifunctional, active burn wound dressings. This review highlights advances in the functionalization of hydrogel dressings for burn care, including fabrication methods, biological efficacy, and therapeutic mechanisms. The literature provides a comprehensive overview of the area where further advancement could be pursued.

Hydrogel-based drug delivery systems are redefining cancer therapy by enabling targeted, biocompatible, and stimuli-responsive treatment strategies. This review examines natural biopolymer hydrogels—such as chitosan, hyaluronic acid, alginate, gelatin, and collagen—and their role in precision oncology. These materials offer biodegradability, tunable properties, and low immunogenicity, supporting controlled drug release. We discuss gelation mechanisms, structural classifications from macrogels to nanogels, and the integration of stimuli-responsive features triggered by pH, temperature, light, and redox conditions within tumor microenvironments. Applications include chemotherapy, radiotherapy, immunotherapy, and phototherapy, using strategies such as passive targeting via the enhanced permeability and retention effect, active targeting via ligand functionalization, and stimuli-triggered release. Cancer-specific implementations in colorectal, gastric, liver, pancreatic, and breast tumors highlight hydrogel versatility. Key challenges include scalability, regulatory compliance, and tumor heterogeneity, while emerging innovations in smart hydrogels, nanotechnology, and personalized medicine offer promising solutions. This review underscores the potential of biopolymer-based hydrogels to advance cancer treatment toward safer, more effective, and patient-centered approaches.