Search Results (1,894)

Rotator cuff tendon injury (RCTI) is aggravated by the pro-inflammatory milieu elicited by TLR4 and TREM1 signaling. Hence, tendon tissue engineering approaches require considerations that address these inflammatory episodes to benefit active regenerative responses. The objective of this study was to engineer and evaluate the immunocompatibility of a tendon-mimetic hydrogel composed of a chitosan–polyvinyl alcohol (PVA) blend incorporated with Collagen-I and to assess LR12 delivery for addressing TREM1-driven inflammation in RCTI management. A chitosan–PVA-HEMA-Acrylic acid (CPHA) hydrogel was synthesized by blending the linear natural polysaccharide chitosan and linear synthetic polymer PVA in an aqueous phase, followed by incorporation and redox chain growth with HEMA using acrylic acid (AA). Interpenetration of Collagen-I in CPHA yielded the CPHA-C hydrogel. CPHA and CPHA-C hydrogels displayed ample surface functional moieties provided by the co-polymers, exhibited excellent porosity as revealed by SEM imaging (28.65 ± 6.85 and 41.56 ± 18.00, respectively, for CPHA and CPHA-C), and were amphiphilic, as evident by contact angle analysis (~70 for CPHA and CPHA-C). Both hydrogels displayed a progressive release profile for the TREM1-inhibitory peptide LR12 for 7 days, whereas the LR12-loaded CPHA hydrogel exhibited increased TREM1 inhibition in LPS-challenged RAW264.7 macrophages. CPHA and CPHA-C hydrogels were immunocompatible and masked the oxidative damage in RAW264.7 macrophages, as evident by decreased levels of mitochondrial superoxide and ROS. Additionally, the CPHA hydrogel displayed an increased TGFβ/TLR4 ratio (0.24), whereas the CPHA-C (−0.52) system showed a decreased ratio upon exposure to tenocytes and macrophages. Overall, the findings highlight the potential of CPHA and CPHA-C hydrogels as candidates for tendon regenerative applications. Full article

Background/Objectives: Cyclic dinucleotide stimulator of interferon genes (STING) agonists have emerged as potential agents in cancer immunotherapy, but their clinical applications are limited by relatively poor pharmacokinetic properties. Methods: A luciferase reporter assay was employed to screen delivery peptides capable of promoting cellular activating effect of cyclic dinucleotide STING agonists. The potent candidates were further confirmed by enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR (qPCR) and Western blotting analysis. Colon and melanoma cancer mouse models were used to examine the antitumor efficacy of the delivery peptides with cyclic GMP–AMP (cGAMP) as a therapeutic agents or vaccine adjuvant. Results: We identify a class of STING agonist delivery peptides that efficiently facilitate cytosolic delivery of cyclic dinucleotide STING agonists and promote STING activation by forming peptide coacervates. Intratumoral administration of Sti3-4A and cGAMP effectively suppressed tumor growth and promoted antitumor immune response. Furthermore, the conjugation of tumor-specific antigen peptides with Sti3-4A promoted cytosolic co-delivery of antigen peptides and cGAMP, thus significantly boosting APC maturation, antigen cross-presentation, and T cell responses to peptide antigens. Prophylactic and therapeutic immunization with the conjugated peptides and cGAMP inhibited tumor growth in multiple murine tumor models. Conclusion: These findings establish STING agonist delivery peptides as a versatile platform for cancer immunotherapy. Full article

Liraglutide (Lira), a glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated substantial efficacy in improving glycemic control and reducing body weight. However, subcutaneous injection is poorly adherent for patients. To improve treatment compliance, we developed a poly(lactic-co-glycolic acid) (PLGA)-based nanovesicle (PLGA-Lira-NV) system for the oral delivery of Lira using a double-emulsion solvent evaporation technique. The optimized formulation yielded a narrow size distribution and high encapsulation efficiency (>95%). In vitro release studies showed that PLGA-Lira-NVs remained relatively stable under acidic conditions (pH 1.2 to 6.8) and exhibited sustained drug release in a neutral environment (pH 7.4), enabling protection of the fragile peptide in the stomach and controlled release after crossing the intestine. Following oral administration to obese mice (10 mg/kg), PLGA-Lira-NVs achieved prolonged glycemic control for up to 72 h. Notably, body weight decreased to 83% of baseline after 12 days, outperforming the subcutaneous injection (free Lira) group (88%). The consistent trend toward weight reduction confirms the sustained-release properties of PLGA nanocarrier for Lira, highlighting its potential to reduce dosing frequency and improve patient compliance. Collectively, these findings underscore the promising potential of PLGA nanovesicles as an oral delivery platform for peptide therapeutics. Full article

Peptide-based supramolecular hydrogels have emerged as promising biomaterials due to inherent biocompatibility, tunable self-assembly, and structural similarity to the extracellular matrix. This work describes the design, synthesis and characterization of a library of symmetrical bolaamphiphiles based on dehydropeptides, systematically varying both the dehydroamino acid residue and the linker. Aromatic and aliphatic dicarboxylic acids with distinct rigidities were employed to elucidate their influence on molecular self-assembly, hydrogelation, and functional performance. Hydrogel formation was triggered using a pH-responsive approach, and critical aggregation and gelation concentrations were determined. Morphological analysis by transmission electron microscopy revealed dense fibrillar networks with nanometer-scale fiber diameters, while rheological studies demonstrated viscoelastic behavior, tunable mechanical strength, and, in selected systems, efficient self-healing properties. The incorporation of phenylalanyldehydrophenylalanine significantly enhanced hydrogel formation, highlighting the importance of π–π interactions and hydrophobicity. Biological evaluation using HaCaT keratinocytes confirmed low cytotoxicity across the series. A representative injectable hydrogel exhibited sustained release of the anticancer drug methotrexate, governed predominantly by Fickian diffusion. These results establish clear structure–property–function relationships and demonstrate the potential of symmetrical bolaamphiphilic dehydropeptides as versatile platforms for controlled drug delivery. Full article

Liquid infant formula has garnered increasing attention due to its mild thermal processing and superior retention of bioactive nutrients. Within such matrices, the lipid source is a critical determinant of protein digestion behavior, yet its influence on peptide bioavailability and intestinal homeostasis remains undefined. Given that efficient peptide absorption is vital for the systemic delivery of bioactivity in infants, understanding the lipid–protein synergy is essential for formula optimization. Moreover, excessive oxidative stress is closely associated with impaired intestinal health and developmental disorders in infants, making the regulation of oxidative stress crucial for maintaining intestinal function. The present study evaluated the effects of three distinct lipid sources—soybean oil (SM), bovine milk fat (BM), and goat milk fat (GM)—on the physicochemical stability, proteolytic digestion, peptide release, intestinal absorption, and oxidative stress modulation of goat-milk-based infant formula. An integrated approach combining physicochemical characterization, in vitro simulated infant digestion, and a Caco-2 intestinal epithelial cell model was employed. we demonstrate that all three lipids (3% w/w) formed stable emulsions with uniform spherical structures and mean particle diameters of 117–300 nm, as visualized by laser confocal microscopy. Following in vitro simulation of infant gastrointestinal digestion, the SM group exhibited the most extensive protein hydrolysis, yielding the highest total peptide content (4.28 ± 0.10 mg/mL) and generated the highest number of peptides identified by LC-MS/MS (474 types). Bioinformatic analysis predicted that peptides from all groups possess potential antihypertensive, hypoglycemic, and immunomodulatory activities. The Caco-2 monolayer cell model demonstrated that although the GM group produced fewer identified peptide species than the SM group (365 types), it achieved significantly higher intestinal peptide absorption rate (55.34 ± 1.05%). Furthermore, the GM digests provided superior protection against H₂O₂-induced oxidative stress in Caco-2 cells, markedly reducing reactive oxygen species levels and suppressing the expression of pro-inflammatory cytokines TNF-α and IL-6. Collectively, these findings reveal that while soybean oil promotes more extensive proteolysis, the use of homologous goat milk lipid enhances peptide bioaccessibility and confers potential cytoprotective effects on intestinal epithelial cells, underscoring its potential as a preferred lipid source in infant formula formulations. Full article

Background: Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne viral disease with a high fatality rate, and no licensed vaccines are currently available. The nucleoprotein (NP) of the Crimean-Congo hemorrhagic fever virus (CCHFV) plays a critical role in viral replication and immune recognition, making it a promising target for vaccine development. This study aimed to design and evaluate a multiepitope recombinant DNA vaccine targeting the NP of CCHFV. Methods: Cytotoxic T lymphocyte (CTL) epitopes from the NP were predicted via immunoinformatics approaches and systematically assessed for antigenicity, allergenicity, toxicity, hydrophobicity, and global population coverage. The selected epitopes were incorporated into four DNA vaccine constructs driven by a cytomegalovirus promoter, adjuvanted with human β-defensin 3 (hBD3), and fused to the reporter protein mRuby3. The constructs were evaluated in vitro using a fluorescent reporter system designed to provide a readout of TCR signaling upon the co-culture of T lymphocytes with differentiated monocytic cells expressing antigens. In vivo immunogenicity and protective efficacy were assessed in BALB/c (exploratory pilot) and IFNAR^−/− mice, a highly susceptible model for viral infection. Cytokine responses were measured to assess immunogenicity. Results: In vitro assays showed predominantly antigen-independent T-cell activation, suggesting that nonspecific stimulation inherent to the reporter co-culture system likely obscured the detection of antigen-specific TCR signaling. In vivo analyses in BALB/c mice revealed that the constructs elicited only modest systemic cytokine profiles while CCHFV-specific IgG and IFN-γ secretion remained undetectable, indicating that antigen-specific T-cell and antibody responses were limited. In the IFNAR^−/− challenge model, several peptide groups achieved significant 2–3 log reductions in tissue viral RNA and infectious titers (p < 0.05 vs. sham). However, the observed viral modulations were insufficient to reach the protective threshold and did not translate to a survival benefit (0%). Conclusion: Despite a rational in silico foundation, the multiepitope DNA vaccine constructs demonstrated limitations in inducing potent, antigen-specific immunity across both mouse models. The lack of antigen-specific responses indicates limitations in epitope selection, construct design, and delivery strategies, requiring optimization of next-generation epitope-based vaccines. These findings highlight the complexity of translating computational epitope predictions into functional vaccines, and provide benchmark data as a framework to guide future optimizations. Full article

Background: This study aimed to investigate, from a scientific and formulation perspective, an oral semaglutide tablet incorporating sodium caprate (C10) as an intestinal absorption enhancer and to optimize its formulation performance using a Quality by Design (QbD)-based approach. Semaglutide—a peptide-based therapeutic—provides effective glycemic control and weight reduction; however, its extremely low oral bioavailability has limited administration to subcutaneous injection. Although various attempts have been made to improve peptide absorption, achieving consistent delivery through oral routes remains a significant challenge due to enzymatic degradation and poor membrane permeability. Methods: To overcome these limitations, an absorption enhancer (sodium caprate) was incorporated to enhance oral absorption, and a Quality by Design (QbD)-based approach was applied to systematically guide formulation development. Following the definition of the Quality Target Product Profile and critical quality attributes, risk assessments (Preliminary Hazard Analysis and Failure Mode and Effects Analysis) were conducted to identify key formulation factors. A design of experiments approach was then employed to determine the optimal tablet composition. Results: Consequently, the resulting formulation met all predefined quality criteria, including hardness, disintegration, friability, and content uniformity. In addition, the in vitro dissolution profile demonstrated a release pattern comparable to that of the reference product, with similarity factor values of 74.4, 74.7, and 71.3 at pH 1.2, 4.0, and 6.8, respectively. Conclusions: These findings indicate that the formulation can achieve consistent and reproducible quality performance as an oral semaglutide dosage form. The QbD-based formulation design strategy presented in this study provides a robust and broadly applicable approach for developing oral delivery systems for peptide drugs, including semaglutide, and ultimately provides useful formulation insight for future peptide-based oral delivery research. Full article

Framework nucleic acids (FNAs) are a class of nucleic acid-based nanostructures characterized by their unique precise structures, excellent biocompatibility and stability, robust loading capacity, and distinctive distribution and metabolic behaviors. They are widely applied in frontier fields such as nanodevices, biosensing, and drug delivery. In recent years, research on FNAs has gradually developed from the design and synthesis of nucleic acid nanostructures to practical applications, particularly in providing precise nanocontainers for heterogeneous molecular drugs such as small molecules, peptides, and proteins. Acting as a drug delivery system, FNA nanocontainers could be utilized to address multiple issues inherent in the application of heterogeneous molecular drugs, including hydrophobicity, affinity, and stability. However, they also face challenges such as low drug carrier capacity, potential immunogenicity, and insufficient long-term stability in vivo, necessitating the development of new strategies. This article focuses on composite drugs of small molecules, peptides, and proteins carried by FNAs, elucidates the design principles of FNA carriers, the interaction modes between FNAs and drug molecules, and the physicochemical properties and biological effects/efficacy of FNA–drug complexes, and summarizes the structure–activity relationship patterns. Furthermore, obstacles limiting clinical transformation are proposed to provide beneficial suggestions for the future development of FNA-based drugs. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory decline, cognitive impairment, and behavioral changes, ultimately leading to a loss of independence and reduced quality of life. Although understanding of the molecular basis of AD has advanced, effective disease-modifying therapies remain scarce. Neuropeptides are small protein-like signaling molecules that regulate diverse physiological processes, including mood, memory, and neuronal function. Growing evidence indicates that neuropeptides are promising therapeutic candidates for AD, particularly through modulation of neuroinflammation, synaptic plasticity, and amyloid-beta (Aβ) aggregation. Preclinical AD models show that neuroprotective neuropeptides, such as neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP), exert neuroprotective effects, enhance memory, and attenuate cognitive decline. This review summarizes current research on neuropeptide-based therapies for AD, detailing their molecular mechanisms, therapeutic actions, and the barriers to their clinical translation. We specifically highlight neuropeptides whose clinical potential in AD remains comparatively underrecognized, discuss strategies for optimizing their delivery and overcoming pharmacokinetic limitations, and outline future perspectives for integrating neuropeptide-based interventions into AD therapy. Full article

This review surveys how nanoparticles and biomolecular nanosized structures interact with model membrane systems, and how these interfacial processes govern their performance in drug and gene delivery, antimicrobial strategies, biosensing, and nanotoxicology. The nanostructures covered include polymeric nanoparticles, lipid-based carriers, peptide nanostructures, dendrimers, and multifunctional hybrids. Model membranes span Langmuir monolayers, supported lipid bilayers, vesicles/liposomes across sizes, and emerging hybrid or asymmetric constructs that better approximate native complexity. Mechanistically, interactions follow recurrent routes—surface adsorption, bilayer insertion, pore formation, and lipid extraction/reorganization—regulated by particle size, morphology, charge, ligand architecture, and lipophilicity, in conjunction with membrane composition, phase state, curvature, and asymmetry. A multiscale toolkit links structure, mechanics, and dynamics: Langmuir troughs and Brewster Angle Microscopy map thermodynamics and mesoscale morphology; atomic force microscopy and quartz crystal microbalance with dissipation resolve nanoscale topography and viscoelasticity; fluorescence microscopy/spectroscopy reports on localization and packing; neutron and X-ray reflectometry quantify vertical structure; molecular dynamics provides atomistic pathways and design hypotheses. Historically, the field advanced from early monolayers and bilayers, through the fluid mosaic model, to raft microdomains and modern biomimetic systems, enabling increasingly realistic experiments. Key advances include cross-method integration linking experimental observations with image-based computational models; persistent debates concern the translation from simplified models to living membranes, the role of dynamic coronas, and scale/force-field limits in simulations. Future efforts should prioritize hybrid models incorporating proteins and asymmetric lipidomes, standardized reporting and reference systems, rigorous coupling of experiments with calibrated simulations and machine learning, and alignment with safety-by-design and regulatory expectations, thereby shifting interfacial measurements from descriptive observation to predictive design rules. Full article

Bone tissue regeneration represents a complex biological process regulated by mechanical, biochemical, and cellular interactions. It remains a major challenge in regenerative medicine due to the limited self-healing capacity of large or complex bone defects. Recent advances have highlighted the pivotal role of biophysical stimuli, such as mechanical loading, electromagnetic fields, ultrasound, and photobiomodulation, in promoting osteogenic differentiation and tissue remodeling. At the same time, bioactive substances, including growth factors, peptides delivered primarily via extracellular vesicles, and biomaterial-based delivery systems, have shown a potential role in enhancing cellular responses and modulating the microenvironment to promote regeneration. This review aims to provide a comprehensive overview of the latest progress in understanding how biophysical and bioactive stimuli converge to regulate bone regeneration and to consider their synergistic approaches that integrate physical stimulation with the controlled release of bioactive molecules. These combined strategies are promising to improve tissue integration and reduce healing times and complications, representing a future research direction. Full article

Cosmetic dermatology has largely focused on topical applications targeting the stratum corneum. However, emerging evidence suggests that visible aging is a systemic readout of internal “organ clocks” and molecular dysregulation across the epidermis and dermis. This review proposes an “inside–out strategy” that seeks to re-conceptualize aesthetic vitality as a measurable indicator of systemic physiological resilience. The author describes theoretically proposed organ–skin axes, including the role of molecular signaling of kidney-derived klotho (KL1 fragment) via FGFR1-α–klotho complexes and muscle-derived irisin through the AMPK/PGC-1-α pathway in modulating skin homeostasis. Drawing on recent breakthroughs in non-human primate models (2023–2025), this synthesis explores the potential of systemic interventions—including nicotinamide adenine dinucleotide (NAD+) precursors (sirtuin 1 SIRT1 activators), senolytics (targeting BCL-2/p16), and glucagon-like peptide-1 (GLP-1) receptor agonists—as candidates to potentially synchronize these internal clocks. Furthermore, the review identifies direct regenerative interventions, such as retinoids (RAR/RXR signaling), chemical peels (HIF-1-α induction), exosomes (miR-21/29 delivery), and poly-L-lactic acid PLLA (mechanotransduction via YAP/TAZ), positioning them as potential physical and chemical epigenetic modulators that may support the restoration of cellular transcriptional fidelity. This article proposes a new paradigm for regenerative aesthetics that focuses on restoring the youthful phenotype by optimizing systemic molecular crosstalk and epigenetic transcriptional fidelity. Full article

Hydrogels and nanocomposite−enhanced hydrogels, owing to their high−water content, excellent biocompatibility, and mechanical flexibility, have demonstrated broad application prospects in tissue engineering, drug delivery, and flexible electronics. With the continuous advancement of computational power, molecular dynamics (MD) simulations have increasingly become an important tool for characterizing nanocomposite materials and hydrogel systems. This approach enables the capture of structural evolution at the atomic/molecular scale and provides mechanistic insights into deformation behaviors and interaction mechanisms under external stimuli such as mechanical force, temperature, and electric fields. This review is organized around the central framework of “structural construction–interfacial regulation−responsive behavior–dynamic evolution”, and systematically summarizes the recent progress in the application of molecular dynamics and multiscale simulation methods to hydrogels and nanocomposite hydrogels. The systems discussed mainly include synthetic polymer-based hydrogels, natural polymer−based hydrogels, peptide/protein−based hydrogels, and nanocomposite hydrogels. Particular emphasis is placed on modeling strategies and force−field selection principles for describing atomic interactions in various nanocomposite hydrogel systems. In addition, the important applications of multiscale simulation strategies in elucidating the interfacial behavior of hydrogels and the mechanisms underlying their dynamic responses under nonequilibrium conditions are also discussed. Finally, future development trends are outlined, including multiscale coupled simulations, closed−loop correction between experiments and simulations, and data−driven modeling strategies for the precise design and performance prediction of complex hydrogel systems. Full article

Background/Objective: Buccal delivery offers a potential route to circumvent gastrointestinal degradation and hepatic first-pass metabolism, but hydrophilic peptides typically exhibit limited mucosal permeation. Nanostructured lipid carriers (NLCs) have been proposed as delivery platforms capable of modulating interfacial interactions and improving mucosal transport. This study aimed to quantitatively evaluate the ex vivo buccal permeation of angiotensin II (Ang II), used as a hydrophilic peptide model, when associated with NLCs compared with free peptide under matched Franz diffusion cell conditions. Methods: Ang II-associated NLCs were prepared by melt emulsification combined with a low-energy injection technique. Particle size, polydispersity index, and zeta potential were determined by dynamic light scattering and laser Doppler electrophoresis. Association efficiency and drug loading were quantified by indirect spectrofluorometric analysis. Ex vivo permeation studies were conducted using porcine buccal mucosa mounted in Franz diffusion cells, and cumulative permeation, steady-state flux, and apparent permeability coefficients were calculated. Results: The NLCs exhibited nanometric size, moderate polydispersity, and association efficiency above 80%, and remained colloidally stable at 4 °C for 28 days. In ex vivo experiments, Ang II-associated NLCs showed measurable cumulative permeation, reaching approximately 9% after 2 h, whereas free Ang II was not detected in the receptor compartment under the tested conditions. Conclusions: This work provides a quantitative ex vivo buccal transport comparison of a hydrophilic peptide model delivered as NLC-associated versus free peptide under matched Franz cell conditions. The findings support further investigation of NLC-based approaches for buccal delivery of vasoactive peptides and provide a rational basis for future in vivo evaluation of mucosal delivery performance and systemic exposure. Full article

Anticancer peptides (ACPs) offer a promising alternative to conventional chemotherapy but face challenges, including poor selectivity, limited tumor penetration, low cellular uptake, and rapid degradation in serum. To address these barriers, we developed synthetic mRNAs encoding chimeric ACPs designed for enhanced intracellular delivery and activity. mRNAs for constructs SAK6L9AS(1X), SAK6L9AS(4X), and WTAS-K6L9(4X) were transcribed in vitro and tested against 4T1 breast cancer cells. Cytotoxicity was assessed by cell confluence and MTT assays, while apoptosis was evaluated using caspase 3/7 activation, PI staining, and Annexin V flow cytometry. Our results demonstrate that all SAK6L9AS variants induced robust apoptosis and cellular toxicity in 4T1 cells. Importantly, this work provides the first demonstration of intracellular expression of an mRNA-encoded ACP fused to a cell-penetrating peptide, thereby validating a modular platform for RNA-based delivery of anticancer agents. This study highlights the feasibility of mRNA-encoded peptide therapeutics as a scalable and customizable strategy for cancer treatment. By combining the advantages of mRNA delivery with rational peptide design, ACP chimeras can be expressed directly inside tumor cells, overcoming the limitations of exogenous peptide administration. Our findings support further development of synthetic mRNA therapeutics to generate potent, selective anticancer peptides with reduced systemic toxicity and improved translational potential. Full article