Stigmasterol-Stabilized Nanoliposomes Enhance Oral Delivery of Collagen Peptides Through Improved Systemic Exposure of Hydroxyproline-Containing Peptides
Aug 2026· Marine Drugs· Vol 24, pp. 293· 0 citations· 43 references
Medicine
TL;DR
It is indicated that stigmasterol-containing nanoliposomes improve the gastrointestinal stability and systemic delivery performance of collagen peptides, providing a promising strategy for enhancing the oral delivery potential of food-derived bioactive peptides.
Abstract
Collagen peptides (CPs) possess diverse biological activities, yet their oral efficacy is limited by gastrointestinal degradation and restricted systemic exposure of intact bioactive peptide species. Herein, a stable cholesterol-free nanoliposome system was developed using soybean phospholipids and stigmasterol through high-pressure microfluidization, followed by tangential flow filtration and spray drying to obtain a stable dry formulation. The optimized nanoliposomes exhibited a particle size below 100 nm, high peptide loading, excellent redispersibility, and remarkable physicochemical stability during refrigerated storage and under different pH and thermal conditions. During simulated gastrointestinal digestion, the stigmasterol-stabilized phospholipid bilayer effectively preserved encapsulated CPs throughout the gastric phase while facilitating peptide release under intestinal conditions. Oral administration in rats significantly enhanced collagen peptide bioavailability, increasing the plasma exposure (iAUC0–8 h) of total hydroxyproline by 3.84-fold compared with free CPs. Peptide-bound hydroxyproline exposure increased 9.3-fold and accounted for approximately 94% of total absorbed hydroxyproline. UHPLC–HRMS analysis confirmed substantially enhanced systemic exposure of multiple characteristic hydroxyproline-containing dipeptides and tripeptides following nanoliposomal delivery. These findings indicate that stigmasterol-containing nanoliposomes improve the gastrointestinal stability and systemic delivery performance of collagen peptides, providing a promising strategy for enhancing the oral delivery potential of food-derived bioactive peptides.
Skin aging is a complex biological process driven by collagen degradation and oxidative damage, often exacerbated by UV exposure. While resveratrol is a premier antioxidant for anti-aging, its topical efficacy is historically limited by poor water solubility and weak skin penetration. This study addresses these barriers by developing optimized polyethylene glycol-based liposomes (PEG-liposomes) as novel deformable liposome derivative. The uncoated vesicles demonstrated high stability and uniformity, with a size of 320.17 ± 0.25 nm and a zeta potential of -35.2 ± 0.4 mV. By coating these vesicles with 0.1% hyaluronic acid (HA), successful surface functionalization and improved size stability was achieved. Ex vivo and confocal studies confirmed that these PEG-liposomes successfully reached the deep dermis; notably, a sequential application strategy of the coated and uncoated PEG-liposomes showed that uncoated vesicles could transiently disrupt lipid structures to facilitate deeper penetration for the HA-coated versions. When integrated with micro-needling via a derma roller, the system triggered significant collagen remodeling and a surge in antioxidant enzymes like SOD, while simultaneously reducing oxidative stress markers such as MDA, MMP-1, and the aging indicator beta-galactosidase. The cooperative effect of this dual-vesicle system not only restored the structural integrity of the dermal-epidermal junction but also significantly outperformed existing commercial resveratrol products. Our findings demonstrate that this novel PEG-liposomal system provides a transformative approach to deep-tissue rejuvenation. Through its unique synergistic mechanism with micro-needling, it achieves biological remodeling and dermal restoration that surpasses the efficacy of current market-leading standards.
Merna Zoweil, Dina Aboushady, Ahmed S. Kamel et al.· European journal of pharmace...· 0 citations
The low oral bioavailability of Dihydromyricetin(DMY), resulting from its instability and poor absorption in the gastrointestinal tract, limits its pharmaceutical applications. In order to enhance the oral bioavailability of DMY, a DMY@CD-CS/TPGS nano-delivery system was successfully prepared using β-cyclodextrin grafted with chitosan (CD-CS) and Tocopheryl Polyethylene Glycol Succinate(TPGS). The DMY@CD-CS/TPGS-NPs have a uniform particle size distribution and good stability. In vitro release studies demonstrated that the NPs exhibited a sustained-release profile under acidic conditions. In vivo and in vitro tests showed that the NPs could promote drug uptake and internalization in Caco-2 cells through multiple endocytic pathways, and disrupt epithelial tight junctions, thereby increasing paracellular absorption. Additionally, it exhibits excellent mucosal adhesion, thereby prolonging drug retention time. The intestinal segment distribution and unidirectional perfusion experiment further demonstrated that the NPs enhanced drug uptake in the duodenum, jejunum, and ileum, and increased both the absorption rate constants and the apparent permeability coefficients. Pharmacokinetic studies demonstrated that DMY@CD-CS/TPGS-NPs significantly enhanced the oral absorption of DMY, increasing the Cmax, AUC0-t, and t1/2 by 7.12-fold, 1.25-fold, and 14.26-fold, respectively. The relative oral bioavailability was 250.39%, representing a 2.50-fold improvement over DMY. Overall, the CD-CS/TPGS nano-delivery system represents a promising strategy for improving the oral delivery of poorly absorbable compounds such as DMY.
Yi-Jin Deng, Rang Yang, Wen-You Ding et al.· European journal of pharmace...· 0 citations
Hydrophobic natural products require delivery systems that protect the payload during gastric transit while preserving intestinal availability. Here, we engineered a hierarchical nanoparticle-in-hydrogel carrier in which thymoquinone (TQ) is first confined within PLGA-PEG nanoparticles, which are then embedded within a pectin-TEOS hydrogel, creating two sequential levels of drug confinement. PEG molecular weight and TEOS concentration were screened to tune network hydration, identifying PEG 6000 and 0.75 M TEOS as the selected formulation. Fourier-transform infrared spectroscopy, thermal analysis, X-ray diffraction and electron microscopy supported polymer integration, reduced crystalline order and incorporation of the nanoparticle compartment within the hydrogel. In SGF, cumulative TQ release at 2 h was 9.6% from directly loaded hydrogel and 5.0% from the nanoparticle-in-hydrogel formulation. Separately measured SIF profiles showed substantial intestinal-phase release. Comparative modelling of the phase-specific datasets indicates that the hierarchical carrier does not act simply as a uniformly slower depot: it suppresses premature gastric loss while permitting TQ release under intestinal conditions. TQ-loaded formulations retained concentration- and time-dependent antiproliferative activity in HeLa and HCT116 cells. Together, these findings support a dual-confinement strategy that couples gastric protection to intestinal TQ availability and provide a basis for further development of pectin-based oral delivery systems.
A. Butt, Numrah Nisar, Atif Islam et al.· Talanta: The International J...· 0 citations
Oral delivery of peptide-based therapeutics remains a major challenge due to enzymatic degradation and poor intestinal permeability. This study reports the development of hybrid zein-Eudragit RS100-chitosan nanoparticles for the co-delivery of insulin and liraglutide (Z-ERS-CS/I-LIRA), aiming to protect both peptides and support their oral administration. The nanoparticles were prepared by nanoprecipitation and exhibited suitable physicochemical properties, including nanoscale size (~230 nm), low polydispersity (PDI < 0.1), and positive zeta potential (~ + 46 mV). Structural and thermal analyses (FTIR, XRD, TGA, and DSC) revealed the formation of a predominantly amorphous and molecularly dispersed system, indicating strong interactions among the polymeric components and effective incorporation of both peptides. The formulation remained stable under refrigerated conditions, showed pronounced mucoadhesive behavior after interaction with mucin, and displayed a biphasic release profile in PBS (pH 7.4), with cumulative release values of approximately 87% for insulin and 58% for liraglutide after 48 h. Under simulated gastrointestinal conditions, minimal peptide release (<15%) was observed, suggesting protection against harsh gastric and intestinal environments. In adult zebrafish, unloaded nanoparticles showed no mortality or significant toxicological alterations, supporting preliminary biocompatibility. In a glucose-induced hyperglycemia model, Z-ERS-CS/I-LIRA reduced blood glucose to levels comparable to healthy controls, preserving antidiabetic activity after encapsulation. However, hemorrhagic and pancreatic alterations in liraglutide-containing groups indicate that further liraglutide dose optimization is required to minimize adverse effects. Overall, Z-ERS-CS/I-LIRA combine peptide protection, mucoadhesion, prolonged release, preliminary in vivo biocompatibility, and antidiabetic activity, representing a promising platform for oral peptide-based combination therapy.
Jeferson Zierbath, T. P. Babinski, Felipe Figueiredo Moreira et al.· International Journal of Bio...· 0 citations
Semaglutide is a glucagon-like peptide-1 receptor agonist widely used for the treatment of type 2 diabetes and obesity. Despite its clinical efficacy, oral administration remains challenging because of its limited gastrointestinal stability, poor epithelial permeability, and low affinity for lipid-based delivery systems. In the present study, a combined hydrophobic ion pairing (HIP) and solid lipid nanoparticle (SLN) approach was explored to improve semaglutide incorporation and delivery-related properties. Semaglutide was complexed with the cationic lipid DOTAP at different molar ratios (1:0-1:18) and subsequently incorporated into cetyl palmitate-based SLNs produced by microfluidic mixing using a herringbone device. The resulting formulations were characterized in terms of particle size, ζ-potential, encapsulation efficiency, morphology, solid-state organization, colloidal stability, release behavior, mucus interaction, cytocompatibility, and epithelial permeability. Among the various formulations prepared, the one prepared with a molar ratio semaglutide: DOTAP of 1:18 and a peptide concentration of 10% (w/w) (F10) showed the best results, combining particle sizes of less than 300 nm with almost complete encapsulation efficiency and a highly positive ζ-potential. FTIR, DSC, TGA and SAXS analyses confirmed the correct formation of the complex and its incorporation into the lipid matrix. The F10 formulation demonstrated good stability under simulated gastrointestinal conditions and a sustained-release profile. The formulation also exhibited strong interactions with mucus, whilst retaining the ability to diffuse through the mucin network. Cytocompatibility studies demonstrated acceptable cell viability at relevant concentrations, whilst permeability experiments through Caco-2 monolayers revealed an approximately 6-fold increase in apparent permeability compared to free semaglutide. Therefore, these findings indicate that the combination of DOTAP-mediated hydrophobic ion pairing and microfluidic-assisted SLN production represents a potentially promising strategy for improving semaglutide encapsulation, gastrointestinal stability, and epithelial transport, while maintaining a favorable balance between mucus interaction and mucodiffusion.
I. Arduino, R. Iacobazzi, Alessia Pontrelli et al.· International journal of pha...· 0 citations
The transdermal delivery of hydrophilic low-molecular collagen peptides (MW ~5 kDa,) remains a major dermatological barrier, owing to the strong barrier function of the stratum corneum. While recombinant collagen peptides holds significant therapeutic promise, its application is severely limited by poor penetration and susceptibility to enzymatic degradation. Herein, we present an interface-engineered strategy based on a therapeutic supramolecular solvent to overcome these limitations. We constructed a supramolecular collagen peptides nanocapsules (Supra-Coll-Nano) system via the non-covalent assembly of α-bisabolol and dipalmitoyl hydroxyproline (DPHP). Unlike conventional inert carriers, this lipid-based supramolecular solvent not only stabilizes recombinant human type III collagen peptides (rhCOL3A1) through precise interfacial modulation but also synergistically regulates the skin microenvironment. The Supra-Coll-Nano exhibited exceptional physicochemical stability and achieved a 22.43-fold increase in viable epidermis collagen peptides deposition compared to free collagen peptides, penetrating to a depth of ~40 μm within 8 h, corresponding to deep viable epidermis. Mechanistically, the system activates the TGF-β1/Smad3 signaling pathway, orchestrating the upregulation of a broad spectrum of collagens (types I, III, IV, VII, XVII, XVIII) and key barrier-associated proteins (Filaggrin, Loricrin), while simultaneously suppressing pro-inflammatory cytokines (TNF-α, IL-1α) via the release of bioactive α-bisabolol. Clinical efficacy evaluations further confirmed these pleiotropic effects, demonstrating significant improvements in stratum corneum hydration (+38.38%) and skin elasticity (+21.57%), along with a remarkable 53.94% reduction in crow's feet wrinkles. This work establishes a new paradigm for "carrier-active" synergistic delivery, offering a robust material strategy for sensitive skin repair and non-invasive anti-aging therapies from molecular design to clinical application.
Mingqing Zhou, An Li, Bo Yang et al.· Journal of Controlled Releas...· 0 citations
