Bioactive peptides and proteins for tissue repair: microenvironment modulation, rational delivery, and clinical potential

Abstract

Bioactive peptides and proteins (BAPPs) are promising therapeutic agents for tissue repair with considerable advantages, including multifunctionality, specificity, biocompatibility, and biodegradability. However, the high complexity of tissue microenvironments and their inherent deficiencies such as short half-live and susceptibility to enzymatic degradation, adversely affect their therapeutic efficacy and clinical applications. Investigating the fundamental mechanisms by which BAPPs modulate the microenvironment and developing rational delivery strategies are essential for optimizing their administration in distinct tissue repairs and facilitating clinical translation. This review initially focuses on the mechanisms through which BAPPs influence the microenvironment for tissue repair via reactive oxygen species, blood and lymphatic vessels, immune cells, and repair cells. Then, a variety of delivery platforms, including scaffolds and hydrogels, electrospun fibers, surface coatings, assisted particles, nanotubes, two-dimensional nanomaterials, and nanoparticles engineered cells, are summarized to incorporate BAPPs for effective tissue repair, modification strategies aimed at enhancing loading efficiencies and release kinetics are also reviewed. Additionally, the delivery of BAPPs can be precisely regulated by endogenous stimuli (glucose, reactive oxygen species, enzymes, pH) or exogenous stimuli (ultrasound, heat, light, magnetic field, and electric field) to achieve on-demand release tailored for specific tissue repair needs. Furthermore, this review focuses on the clinical potential of BAPPs in facilitating tissue repair across various types, including bone, cartilage, intervertebral discs, muscle, tendons, periodontal tissues, skin, myocardium, nervous system (encompassing brain, spinal cord, and peripheral nerve), endometrium, as well as ear and ocular tissue. Finally, current challenges and prospects are discussed.

Keywords: Bioactive peptides and proteins (BAPPs); Clinical potential; Delivery strategies; Growth factors; Tissue regeneration.

Fig. 1

Overview of bioactive peptides and proteins (BAPPs). a Microenvironment modulation, including ROS, blood and lymphatic vessels, immune cells, and repair cells. b Delivery platforms comprising electrospun fibers, coatings, two-dimensional nanomaterials, nanoparticles, engineered cells, scaffolds, hydrogels, assisted carriers, and nanotubes. c Stimuli-responsive delivery mechanisms involving endogenous stimuli, magnetic field, electric field, heat, light, and ultrasound. d Clinical potential encompassing preclinical studies utilizing cell culture and animal models alongside clinical trials, as well as approval and supervision. ROS reactive oxygen species, MMP matrix metalloproteinases, IL interleukin, IFN-γ interferon-γ, Th helper T cell, Treg regulatory T cells, TGF-β transforming growth factor-β

Fig. 2

BAPPs regulate the ROS family during physiological and pathological processes. a Physiological function of reactive oxygen species (ROS). b Bioactive peptides and proteins (BAPPs) for scavenging ROS and other free radicals in osteoarthritis, diabetes, wound healing, and neurodegenerative diseases. VEGF vascular endothelial growth factor, FGF fibroblast growth factors, IL interleukin, PaT-2 FPPWL-NH2, HA hyaluronic acid, RNS reactive nitrogen species, NOX NADPH oxidases, ATP adenosine 5’-triphosphate, ADP adenosine diphosphate, TCA tricarboxylic acid cycle, Cyt C cytochrome C

Fig. 3

Bioactive peptides and proteins (BAPPs) for blood and lymphatic vessel regeneration. PDGF platelet-derived growth factor, Ang-1 angiopoietins-1, TGF-β transforming growth factor-β, VEGF vascular endothelial growth factor, QK KLTWQELYQLKYKGI, FGF fibroblast growth factors, VSMCs vascular smooth muscle cells, ET-1 endothelin-1, HIF-α hypoxia-inducible factor-α, IGF insulin-like growth factor, CXCL chemokine ligand C-X-C motif chemokine ligand

Fig. 4

Bioactive peptides and proteins (BAPPs) for immune cell. For innate immune cells, BAPPs regulate the pro-inflammatory and anti-inflammatory balance of neutrophils, monocytes, and macrophages primarily by acting on these cells. In the case of adaptive immune cells, BAPPs similarly modulate the proinflammatory and anti-inflammatory balance of T cells with various phenotypes as well as macrophages by predominantly targeting these cells. PGRN progranulin, ATSTTRIN proper noun, APET ASIC3 inhibitory peptide, MLIF monocyte locomotion inhibitory factor, VEGF vascular endothelial growth factor, QK KLTWQELYQLKYKGI, IL interleukin, LASLT proper noun, LPS lipopolysaccharide, PEP-B synthetic human β-defensin 1 short motif, TNFR tumor necrosis factor receptor, TNF tumor necrosis factor, IFN interferon, GM-CSF granulocyte–macrophage colony-stimulating factor, GLP glucagon-like peptide, VIP vasoactive intestinal polypeptide, IGF insulin-like growth factor, PDGF platelet-derived growth factor, CX3L the chemokine (C-X-C motif) ligand, MHC major histocompatibility complex, TCR T cell antigen receptor, Th helper T cell, Treg regulatory T cells, DPEP dipeptidase

Fig. 5

Bioactive peptides and proteins (BAPPs) for cell survival and cell senescence. a Bcl-2 family, MCP-1 and 7A inhibit cell apoptosis. b Ospc3 inhibits cell pyroptosis through caspase-4/5/11. c FSP-1 inhibits lipid peroxidation, thereby inhibiting ferroptosis. d Potential pathways to inhibit cell necroptosis. e ANKB-LIR, ANKG-ER, and PTH 1-34 modulate autophagy balance in neurodegenerative diseases, osteoporosis, and osteoarthritis. ANKB-LIR ankyrin-B extended LIR motif, ANKG-ER ankyrin-G extended E1991R LIR motif, PTH 1-34 parathyroid hormone-related peptide 1–34. f TGF-β1, BMP-4, and IGFBP-7 inhibit cell senescence. BAX BCL2-Associated X, BAK BCL2-Associated K, MCP-1 monocyte chemotactic protein-1, 7Ap phosphorylated HDAC7-derived peptide 7A family, Bcl B-cell lymphoma, Ras-Erk1/2 Ras-extracellular signal-regulated kinases1/2, IL interleukin, DAMPs damage-associated molecular patterns, PAMPs pathogen-associated molecular pattern, LPS lipopolysaccharide, GSDMD gasdermin D, OspC3 Shiga bacterial effectors, GPX glutathione peroxidase, NCOA4 nuclear receptor coactivator 4, FSP-1 ferroptosis suppressor protein-1, TNFR1 tumor necrosis factor receptor1, FAS factor-related Apoptosis, TRAILR tumor necrosis factor-related apoptosis-inducing ligand, RIPK receptor-interacting protein kinase 1, ZBP-1 Z-DNA binding protein 1, MIKL mixed lineage kinase domain-like protein, PTH parathyroid hormone, ANKB-LIR ankyrin-B motif, ANKG-ER ankyrin-K motif, BMP-4 bone morphometric proteins-4, IGFBP-7 IGF binding protein-7, TGF-β transforming growth factor β, SASP senescence-associated secretory phenotype, TRIF Toll/IL-1 receptor (TIR) domain-containing adaptor

Fig. 6

Bioactive peptides and proteins (BAPPs) for repair cells in cell recruitment, cell adhesion, cell proliferation, and cell differentiation. a SDF-1, E7, substance P, and BMHP1/2 modulate the recruitment of MSCs, EPSCs, and NSCs through the PI3K-Akt and Ras-Erk1/2 pathways. b PHSRN, RGD, NCAM, and other cell adhesion peptides modulate cell adhesion through integrin-αvβ3 α2β1, α4β1, and IgSF. c HGF, EGF, TGF-β, NGF, and other BAPPs modulate cell proliferation through the PI3K-Akt and Ras-Erk1/2 pathways. d PDCD5, TGF-β, IGF-1, BMP-2, P24, P20, PTH, PTHrP 1/2, OGP, osteostatin, and other BAPPs modulate cell differentiation through the Smad, Ras-Erk1/2, WNT, and MAPK pathways. SDF-1 stromal cell-derived factor-1, E7 EPLQLKM, CXCR-4 chemokine receptor type 4, PI3k-Akt phosphoinositide 3-kinase-protein kinase B, NK-1R neurokinin-1 receptor, DGEA collagen I-derived peptide, RGD adhesion peptide, PHSRN synergy peptide, NCAM neural cell adhesion molecule, PDCD5 programmed cell death 5, TGF-β transforming growth factor-β, POSTN periostin, BMP bone morphogenetic protein, bFGF basic fibroblast growth factor, IGF-1 insulin-like growth factor-1, PTH parathyroid hormone, PTHrP parathormone related peptide, OGP osteogenic growth peptide, BIFP binding-induced fibrillogenesis peptide P, BIFY binding-induced fibrillogenesis peptide Y, MAPK mitogen-activated protein kinases, RANK receptor activator of nuclear factor-kappa B, FGF fibroblast growth factor, HGF hepatocyte growth factor, EGF epidermal growth factor, PDGF platelet-derived growth factor, NGF nerve growth factor, BDNF brain-derived neurotrophic factor, CGRP calcitonin gene-related peptide

Fig. 7

Distinctive delivery platforms coupled with modification strategies for tissue repair. a Scaffolds and hydrogels; Strategies to improve affinity for bioactive peptides and proteins (BAPPs), including glycosaminoglycans (GAGs) and sulfated polymers, fibronectin and derivatives, affinity peptides and affibodies, and aptamers. b Types of electrospun fibers (blending, coaxial, and emulsion) and delivery strategies by encapsulation and adsorption. c Distinctive surface coatings for delivery, including polydopamine coatings, metal-phenolic network coatings, extracellular matrix (ECM) coatings, layer-by-layer self-assembly coatings, electrophoretic deposition coatings, mineral coatings, and engineered functional coatings. d Delivery strategies for assisted particles, including surface adsorption, covalent grafting, coprecipitation during synthesis, inner capsulation, binding molecules, surface coatings, and electrospraying. e Delivery strategies for nanotubes by surface adsorption, inner capsulation, and covalent grafting; delivery strategies for TiO₂ nanotubes include surface adsorption, microsphere capsulation, surface coating, and surface sealing. f Delivery strategies for two-dimensional nanomaterials, including surface adsorption, covalent grafting, surface coatings, and layered encapsulation. g Nanoparticles engineered cells for delivery by encapsulation and adsorption. FN fibronectin

Fig. 8

Stimuli-responsive delivery of bioactive peptides and proteins (BAPPs) for tissue repair. a Endogenous stimuli from the microenvironment (glucose, ROS, the MMP, and pH) and the corresponding chemical bond breaks in response. b The coordination bond between calcium and alginate is broken under ultrasonic stimulation; ultrasound stimulates PFC droplets to vaporize into microbubbles, which triggers response release. c When the temperature is higher than the lower critical solution temperature (LCST), the volume of the thermosensitive polymers decreases. Then, the micromolecular agents are squeezed out, while the macromolecular agents are fixed by contracted thermosensitive polymers. d The photosensitive group is broken under ultraviolet and visible light stimulation; near-infrared light produces photothermal effects that trigger volume shrinkage of thermosensitive polymers. e AMF triggers magnetic nanoparticles to generate heat; SMF triggers magnetic nanoparticles to move and induces hydrogel deformation. f When an electric current is applied, the drug-loaded conjugated polymer undergoes a redox reaction, which changes its properties, leading to the release of BAPPs. ROS reactive oxygen species, MMP matrix metalloproteinases, US ultrasound, SMF stationary magnetic field, PFC perfluorocarbon, AMF alternating magnetic field

Fig. 9

Clinical potential of bioactive peptides and proteins (BAPPs) for various tissue repair and critical steps for their clinical translation. BAPPs demonstrate significant potential for the clinical repair of a wide range of tissue, including bone, cartilage, intervertebral discs, muscle, tendons, periodontal tissue, skin, myocardial tissue, nervous system tissue, endometrium tissue, as well as ear and ocular tissue. In alignment with the critical steps necessary for their clinical translation, BAPPs are typically evaluated in preclinical studies through sequential cell culture followed by testing in small and large animals after the initial identification, design and functional analysis. Subsequently, they undergo evaluation via clinical trials from phase I to phase IV until receiving approval for market entry