Search Results (2,315)

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss worldwide and is driven by complex pathophysiological processes, including oxidative stress, chronic inflammation, complement dysregulation, and vascular endothelial growth factor (VEGF)-mediated neovascularization. Nutritional interventions—particularly supplementation with carotenoids, omega-3 fatty acids, polyphenols, and essential micronutrients—have demonstrated clinical benefits in slowing disease progression, as evidenced by landmark trials such as AREDS and AREDS2. However, many AMD-relevant bioactives exhibit poor aqueous solubility, low chemical stability, and limited gastrointestinal bioavailability, which significantly constrain their therapeutic efficacy. Food-grade microgels have emerged as versatile colloidal delivery platforms capable of addressing these limitations through rational structural and physicochemical design. This review provides a systematic roadmap for developing food-grade microgels, organized into: (1) the molecular design of protein- and polysaccharide-based networks; (2) advanced fabrication strategies such as microfluidics and atomization; (3) spatiotemporal release programming within the gastrointestinal tract; and (4) multi-nutrient synergy for retinal protection. This approach highlights how controlled crosslinking, interfacial assembly, and tunable network architectures enhance nutrient stabilization. Particular emphasis is placed on spatiotemporal release programming within the gastrointestinal tract, including diffusion-limited gastric retention, pH- and bile-responsive swelling in the small intestine, and microbiota-triggered degradation in the colon. These mechanisms collectively enable region-specific release, improved micellar incorporation, enhanced systemic absorption, and more consistent retinal delivery. Furthermore, we discuss co-encapsulation strategies that accommodate both hydrophilic and lipophilic bioactives, thereby minimizing antagonistic interactions and enabling synergistic nutritional modulation of oxidative and inflammatory pathways implicated in AMD. A central novelty of this review is the integration of the gut–eye axis, framing microgel-based oral delivery as a systemic pathway to modulate retinal health via the intestinal environment. By bridging retinal disease biology with food colloid science, this review proposes food-grade microgels as a translational platform for next-generation nutraceutical interventions. The integration of programmable release behavior with clinically validated nutrient regimens offers a promising pathway toward more effective and mechanistically informed dietary management of AMD. Full article

Background/Objectives: Cholestasis is a clinically intractable liver disorder. Da-Huang-Xiao-Shi Decoction (DHXSD), a classic traditional Chinese medicine formula, demonstrates notable efficacy, yet the mechanistic basis for its multi-herb synergy remains unclear. The purpose of this study was to decipher the pharmacokinetic interaction underlying the synergy of DHXSD. Methods: A cholestatic rat model was established in male Sprague Dawley rats. Hepatoprotective efficacy was evaluated, and the pharmacokinetics of anthraquinones were profiled. Key interaction mechanisms were investigated using the everted intestinal sac model, the breast cancer resistance protein (BCRP)-overexpressing MDCKII cells, and molecular docking simulations. Results: DHXSD provided significantly stronger hepatoprotection than its principal herb Rheum palmatum L. (DaHuang, DH) alone. This enhanced efficacy correlated with an approximate 2-fold increase in the systemic exposure of rhein compared to DH monotherapy. We identified berberine from Phellodendron amurense Rupr. (Huang Bo, HB) as the key synergist, which potently inhibited the BCRP efflux transporter, thereby enhancing rhein absorption. In contrast, geniposide from Gardenia jasminoides Ellis (Zhi Zi, ZZ) showed minimal effects. Conclusions: This work elucidates a concrete, transporter-mediated pharmacokinetic interaction as the core mechanism underlying herbal synergy in DHXSD. Our findings offer a rational strategy—targeted efflux transporter modulation—for improving the oral bioavailability of challenging drug molecules. Full article

Plant-derived extracellular vesicles (PDEVs), engineered phytosomes, bioinspired polymeric plant-based nanoparticles (PBNPs), hybrid phyto-inorganic nanocomposites, green-synthesized metal nanoparticles, self-assembled nanoarchitectures, and multifunctional composites represent a rapidly advancing class of sustainable, nature-inspired nanocarriers. These platforms combine exceptional biocompatibility, negligible immunogenicity, and renewable sourcing with tunable drug loading, targeted delivery, and controlled release properties. This review synthesizes translational advances from 2020 to 2026, covering scalable isolation/bioprocessing (bioreactors, elicitation), multi-parametric physicochemical/multi-omics characterization, rational engineering/hybridization, and rigorous in vitro/in vivo assessments of uptake, biodistribution, pharmacokinetic (PK), and efficacy. Phytosomes and PBNPs markedly enhance oral bioavailability and targeted delivery of lipophilic phytochemicals, while PDEVs offer unique immunomodulatory, anti-inflammatory, and gene-regulatory activities. Hybrid and green-synthesized systems provide structural stability, redox modulation, and synergistic effects, and self-assembled/multifunctional composites address solubilization barriers with stimuli-responsive design. Early-phase human studies on grapefruit-, ginger-, turmeric-, and ginseng-derived PDEVs report excellent short-term safety, favorable PK, and preliminary bioactivity signals, with no observed immunogenicity or dose-limiting toxicities; however, these trials remain exploratory, constrained by small sample sizes and safety-focused endpoints. Despite challenges, including methodological heterogeneity, variable yields, long-term safety uncertainties (notably for inorganic hybrids), and regulatory ambiguities, emerging strategies such as clustered regularly interspaced short palindromic repeats (CRISPR)-engineered plant line; artificial-intelligence-driven process optimization; standardized guidelines, and integrated clinical, intellectual property, and commercialization frameworks are progressively addressing these barriers. Collectively, these advances position plant-derived nanocarriers as immunologically privileged, eco-friendly alternatives to synthetic and mammalian platforms, laying the foundation for a sustainable era of precision phytomedicine. Full article

Objectives: Rhizoma Coptidis alkaloids (RCAs) have been proven highly promising in diabetes therapy. However, poor solubility, low bioavailability, and a lack of an effective delivery strategy are major hurdles to improving clinical outcomes. Herein, mPEG-PLGA nanoparticles were employed to deliver RCA orally to enhance anti-diabetic effects. Methods: The RCA-loaded nanoparticles (RCA NPs) were prepared using the emulsion solvent diffusion method. The physicochemical properties of RCA NPs were characterized by morphology, particle size, zeta potential, polydispersity index, drug loading, and drug release. Pharmacokinetic and tissue distribution were determined by UPLC-MS/MS. The hypoglycemic effect was evaluated in a type 2 diabetes mouse model. To illustrate potential mechanisms of action, the expression of PI3K/Akt signaling pathway-related genes and their proteins was detected by RT-PCR and Western blot, respectively. Results: The prepared RCA NPs were spherical in structure, with a particle size of approximately 145 nm and a sustained drug release profile (approximately 50% within 24 h). Compared with RCAs, RCA NP bioavailability increased approximately 2.2-fold, and the hypoglycemic, hypolipidemic, hepatoprotective, anti-inflammatory effects were significantly improved. The better outcome might be due to upregulation of expression and phosphorylation levels within the IRS1/PI3K/AKT/GLUT4 signal pathway in liver tissues. Conclusions: RCA NPs hold great potential for further clinical translation. Full article

Biomarker-based guided delivery of drugs is an emerging paradigm of precision medicine in which targeted therapeutic intervention is administered on the basis of certain biological markers in order to achieve maximal dosing, targeting, and time optimization. By utilizing quantifiable physiological or molecular signatures like the expression of transporters, enzymatic activities, metabolite levels, or disease-specific markers to tie in the correlation of drug disposition, these systems provide individualized intervention with optimized efficacy and safety. Oral administration of drugs is still the best route in patient compliance; however, several drugs are handicapped by suboptimal bioavailability secondary to poor solubility, limited permeability, efflux transporter participation, and enzymatic first-pass degradation. These result in variable therapeutic results in patient populations. Biomarker guidance in oral drug delivery provides a potent strategy for overcoming such challenges through site-specific release, real-time dose optimization, and adjustment of absorption pathways. Recent developments include pH-controlled formulations for gut-specific targeting, enzyme-activated nanocarriers, glucose-starved responsive devices for metabolic disease, and biomarker-driven transporters for permeability enhancement. Preclinical and early-phase clinical studies hold promising prospects for applications in oncology, infectious disease, inflammatory bowel disease, and metabolic disease. While promising momentum exists, transition to routine use in the clinic awaits rigorous biomarker validation, scalability in manufacture, and regulations harmonization. On the horizon, the integration of biomarker-guided oral drug delivery with nanotechnology, artificial intelligence, machine learning, and wearable biosensors holds promise for revolutionizing oral therapy into very personalized, responsive, and efficient treatment methods. Full article

Glutathione (GSH), often referred to as the “master antioxidant,” plays a vital role in protecting cells against oxidative stress. This human pilot study aimed to evaluate the oral absorption and safety profile of a novel formulation of micellar glutathione (LipoMicel^®, LMG) compared with two commonly used dietary supplement forms: standard glutathione (STD) and liposomal glutathione (Setria^® Glutathione, LSG). In the first phase, a randomized, double-blind, crossover study was conducted in healthy adults (n = 14) to assess whole-blood GSH following single oral doses using baseline-adjusted pharmacokinetic parameters (incremental AUC_0–24 [iAUC_0–24], C_max, T_max) and a targeted panel of glutathione-related metabolites. In the second phase, a 30-day, single-arm follow-up assessed the safety and tolerability of the most bioavailable formulation (LMG) in the same participants. Compared with STD (500 mg), LMG (300 mg) produced significantly higher baseline-adjusted systemic GSH exposure and peak response (iAUC_0–24: 1287.5 ± 179.0 vs. 517.8 ± 180.0 µg·mL·h; p = 0.0064; ΔC_max: 103.9 ± 11.8 vs. 42.8 ± 11.5 µg/mL; p = 0.0003), corresponding to ~2.49-fold higher incremental exposure and ~2.43-fold higher peak response at the administered doses. When dose-normalized to a 300 mg equivalent, the incremental exposure (iAUC) and C_max were up to 4-fold higher for LMG than STD. In the targeted metabolite panel, most analytes showed no formulation-dependent differences; however, dose-normalized methionine exposure was significantly higher with LMG than STD (iAUC: 149.9 ± 30.8 vs. 32.7 ± 28.3 µg·mL·h; p = 0.0151; ~4.58-fold). No significant differences were observed in oxidized glutathione (GSSG) exposure, while the GSH/GSSG ratio was higher following LMG versus STD (p = 0.001). No significant changes in clinical safety markers (e.g., ALT, AST, ALP, creatinine) were observed following 30 days of daily LMG administration at 600 mg/d. The novel micellar glutathione formulation demonstrated enhanced oral bioavailability compared with a standard glutathione preparation and was well tolerated over 30 days in healthy adults. These findings present LipoMicel^® as a promising approach for oral glutathione delivery and warrant further investigation into its long-term physiological and clinical effects. This clinical trial was registered at ClinicalTrials.gov under trial ID NCT06345950 on 3 April 2024. Full article

Background: Gefitinib (Gef) is a first-line epidermal growth factor receptor (EGFR) inhibitor for NSCLC, but its clinical application is limited by poor aqueous solubility and low oral bioavailability. Methods: A self-assembled gefitinib nanosuspension (GG-NS) incorporating genistein (Gen) was rapidly developed and optimized via hammer acoustic resonance (HAR) technology. Systematic optimization was conducted using a high-throughput HAR-based process, with particle size, PDI, and zeta potential as key evaluation parameters. Structural and morphological characteristics were analyzed using powder X-ray diffraction (PXRD), thermal analysis, transmission electron microscopy (TEM), and Fourier-transform infrared (FT-IR) spectroscopy. In vitro dissolution behavior and cytotoxicity against A549 lung cancer cells were evaluated. Results: Optimal GG-NS with Z-Ave = 223.50 ± 1.53 nm, PDI = 0.239 ± 0.031 and zeta potential = −24.10 ± 0.47 mV was successfully prepared. The nanosuspension remained physically stable for up to five months at both 4 °C and 25 °C. Compared with the raw drugs, GG-NS enhanced the dissolution of gefitinib and genistein in water by 3.76-fold and 13-fold, respectively. In addition, GG-NS showed significantly enhanced cytotoxicity against A549 cells, with a 33.8% higher inhibition rate than the physical mixture after 72 h. Conclusions: This study demonstrates, for the first time, that HAR technology enables the rapid fabrication of a self-assembled GG-NS with improved dissolution performance, physicochemical stability, and in vitro anticancer activity, highlighting its promise as an efficient and scalable formulation strategy for poorly soluble anticancer drugs. Full article

Background: Myricetin (MYR) is a natural flavonol with antioxidant, neuroprotective, anti-inflammatory, antidiabetic, and cardioprotective activities. Still, its pharmaceutical use is limited by very low aqueous solubility (~16.6 µg/mL) and poor oral bioavailability (<10%). This study aimed to enhance the solubility and potentially improve the bioavailability of MYR by developing an amorphous nanofibrous delivery system. Methods: Electrospinning was applied to fabricate MYR-loaded nanofibers using polyvinylpyrrolidone K30 (PVP30), and the influence of key processing parameters on MYR solubility was evaluated. Nanofibers produced under selected electrospinning conditions were characterized in terms of morphology, encapsulation efficiency, and physicochemical properties. Results: X-ray powder diffraction confirmed complete amorphization of MYR within the BB5 fiber structure (distance: 12 cm, voltage: 25 kV, flow rate: 1.5 mL/h). FTIR analysis indicated hydrogen-bonding interactions between MYR hydroxyl groups and PVP30 carbonyl groups, contributing to stabilization of the amorphous form. SEM images revealed homogeneous, defect-free fibers with diameters below 400 nm, although localized MYR agglomerates were observed. Solubility and release studies demonstrated a characteristic spring-and-parachute effect, enabling rapid MYR release and maintenance of a supersaturated state. Enhanced solubility resulted in significantly improved antioxidant activity in DPPH and CUPRAC assays compared with crystalline MYR. Conclusions: Electrospun PVP30 nanofibers represent a promising platform for improving the solubility, dissolution behavior, and functional activity of poorly soluble bioactive compounds such as myricetin, supporting their potential application in pharmaceutical formulations. Full article

Background/Objectives: Current clinical evidence suggests that cannabidiol (CBD) demonstrates therapeutic potential in the management of chronic pain, particularly in conditions involving inflammation. However, its therapeutic potential is severely limited by poor oral bioavailability, extensive first-pass metabolism, and the need for frequent high-dose administration, which compromises patient adherence and tolerability. Long-acting injectable (LAI) delivery systems offer a strategy to overcome these limitations by providing sustained plasma concentrations and reducing dosing frequency. This study aimed to develop and optimise CBD-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres for LAI delivery and to evaluate poly(2-ethyl-2-oxazoline) (POx) as a functional and biocompatible alternative to the conventionally used poly (ethylene glycol) (PEG). Methods: CBD-loaded microspheres were prepared using emulsion–solvent evaporation technique. The formulations were optimised based on entrapment efficiency (EE), drug loading (DL), particle size distribution, surface morphology, thermal behaviour, in vitro release kinetics, and cytocompatibility using NIH 3T3 fibroblasts. Multiple in vitro release methodologies, including dialysis bag, shaking-flask, and USP Apparatus IV, were evaluated to identify the most discriminative and practical approach for long-term release assessment. Results: The optimised POx-based microspheres demonstrated superior control over particle size, yielding significantly smaller and more uniform particles compared with PEG-based microspheres (124 ± 1.47 µm vs. 218 ± 13.5 µm, respectively). Differential scanning calorimetry (DSC) confirmed molecular dispersion of CBD within the polymer matrix. In vitro release studies demonstrated sustained drug release over 20 days. Conclusions: POx represents a promising alternative to PEG for the formulation of CBD-loaded PLGA microspheres, offering enhanced physicochemical stability and biological compatibility. This platform supports the development of safe and effective long-acting injectable CBD therapies and consideration of POx as an alternative to PEG. Full article

Imperatorin, a naturally occurring furanocoumarin found in several medicinal plants, has attracted considerable scientific interest due to its broad spectrum of pharmacological activities and emerging relevance in oncology. In recent years, an increasing number of experimental studies have investigated its biological effects and molecular mechanisms across different tumor models. Due to this, the review synthesizes the current preclinical and pharmacological evidence on imperatorin in cancer, with the aim of consolidating the main mechanistic pathways involved in its antitumor activity, identifying its therapeutic opportunities, and highlighting existing challenges and future research perspectives. Available in vitro and in vivo studies demonstrate that imperatorin exerts multi-targeted antitumor effects, including the induction of apoptosis, inhibition of proliferation, suppression of angiogenesis, modulation of oxidative stress, attenuation of inflammation, and disruption of oncogenic signaling pathways such as PI3K/Akt, MAPK, mTOR, and NF-κB. Imperatorin also influences the tumor microenvironment by reducing pro-inflammatory mediators, impairing stromal–tumor cross-talk, and enhancing immune-cell-mediated cytotoxicity. In addition, we also summarize pharmacokinetic and safety limitations that hinder clinical translation, including low oral bioavailability, extensive plasma protein binding, cytochrome P450 interactions, and insufficient toxicological data. In parallel, we highlight recent advances in the genetics and biosynthesis of imperatorin, which support perspectives for sustainable production and structural optimization of imperatorin derivatives. Finally, we outline key knowledge gaps and future directions, including improved delivery strategies, investigation of additional regulatory pathways, and more robust in vivo and translational studies, emphasizing that imperatorin remains a promising yet still incompletely characterized anticancer candidate. The review highlights the need for more comprehensive pharmacokinetic and safety assessments, as well as the development of improved delivery systems to address absorption and stability challenges. Further research into imperatorin’s effects on autophagy, ferroptosis, metabolic reprogramming, and the immune microenvironment is essential to deepen mechanistic understanding. Additionally, fully elucidating the biosynthetic enzymes responsible for imperatorin formation may facilitate sustainable production and the design of structurally optimized analogs. Full article

Respiratory syncytial virus (RSV) poses a substantial global health burden, particularly in infants and the elderly. The fusion (F) protein is a key therapeutic target for inhibiting RSV entry. In this study, we performed a structure-based virtual screening of the Comprehensive Marine Natural Products Database (CMNPD) to discover novel anti-RSV agents targeting the prefusion F protein trimer. Screening of 31,561 compounds via molecular docking, followed by stringent ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling and MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) binding free energy calculations, identified 11 promising candidates. Among these, manzamine alkaloids exhibited the most favorable docking scores (as low as −13.3 kcal/mol) and promising Ligand Efficiency (LE) values. These molecules primarily interact with conserved hydrophobic residues (Phe140, Phe488) through hydrophobic interactions, π-stacking, and electrostatic forces. Our study highlights marine natural products, especially manzamine alkaloids, as promising leads for the development of novel, orally bioavailable RSV fusion inhibitors, potentially offering avenues to overcome existing drug resistance. However, these computational findings require in vitro validation to confirm efficacy. Full article

This study assesses the stability, in vitro bioaccessibility and potential bioavailability, and in vivo genotoxicity and toxicity of polyethylene glycol–soy lecithin (PEGSL-ACG-NSps) or β-cyclodextrin–soy lecithin (βCDSL-ACG-NSps) nanosuspensions (NSps). Both formulations exhibited initial particle sizes below 130 nm and PDI values below 0.3. Under simulated gastrointestinal conditions, PEGSL-ACG-NSps preserved structural integrity, with only a moderate size increase (~239 nm) in the intestinal phase and controlled release of acetogenins (ACGs); in contrast, βCDSL-ACG-NSps destabilized considerably (size > 500 nm) and released ACGs rapidly. Consistently, βCDSL-ACG-NSps achieved higher in vitro bioaccessibility and a potential bioavailability (up to 95% from post-digestion recovery). In contrast, PEGSL-ACG-NSps displayed a more gradual release profile (up to 55%). In vivo toxicity tests in mice showed no significant genotoxic or cytotoxic effects for either formulation, even at high doses. These findings suggest that selecting appropriate food-grade stabilizing polymers is crucial for optimizing NSps for the oral delivery of ACGs as therapeutic agents. Full article

In this narrative review, we address the prevention and therapy of iron deficiency anemia (IDA) with oral iron products in pediatric patients. Fortification of complementary foods with iron-containing micronutrient powders is the preferred method for the prevention of IDA in resource-limited settings. In developed countries, the prevention of sideropenia is through the consumption of iron-rich foods of animal origin. Regarding oral iron therapy, ferrous sulfate is the most widely used and cheapest product, but it is less well tolerated due to gastrointestinal side effects compared to complexes of ferric iron with polysaccharides, and complexes of iron with amino acids in casein, such as iron protein succinylate and iron acetyl aspartylate. These latter products are expensive and available only as single-dose vials with a fixed amount of elemental iron. Intermittent administration of ferrous sulfate, once or twice a week, is equally effective to daily therapy, with fewer side effects, and can be used in selected patients. Oral carbonyl iron has excellent bioavailability and the additional advantage of a high safety margin in cases of accidental overdose compared to iron salts, an important consideration given the potentially lethal consequences of iron overdose. Newer liposomal and sucrosomial iron products appear to have better intestinal tolerance and similar efficacy in the treatment of IDA, but limited pediatric data exist. In conclusion, all oral medicinal iron products are effective when prescribed for the treatment of IDA, if well-absorbed and taken consistently for 3 to 6 months. Physicians should be prepared to use alternative oral agents with better tolerance in case of gastrointestinal side effects. Full article

Chrysanthemum indicum L. (C. indicum), a perennial herb widely distributed across East Asia, has long been utilised in traditional medicine and as a functional food ingredient. Contemporary research has revealed a chemically diverse phytochemical profile, dominated by flavonoids, phenolic acids, sesquiterpene lactones, essential oils, carotenoids, and polysaccharides, which collectively underpin its broad pharmacological potential. Experimental studies demonstrate that extracts and isolated constituents of C. indicum exert pronounced antioxidant, anti-inflammatory, antimicrobial, hepatoprotective, cardioprotective, and anticancer effects in vitro and in vivo, often through modulation of key molecular pathways such as NF-κB, NLRP3 inflammasomes, AMPK–SIRT1, and Nrf2 signalling. Emerging pharmacokinetic evidence indicates variable oral bioavailability and metabolic transformation of major bioactive compounds, highlighting formulation challenges that may influence therapeutic efficacy. Toxicological studies suggest a generally favourable safety profile at traditionally used doses, although long-term and clinical safety data remain limited. Regulatory positioning varies internationally, with applications spanning traditional herbal preparations, dietary supplements and functional foods. Despite promising preclinical findings, significant challenges persist, including chemical standardisation, bioavailability optimisation, mechanistic clarification and the paucity of well-designed clinical trials. This review critically synthesises current knowledge on the botany, phytochemistry, pharmacological activities, pharmacokinetics, safety considerations and regulatory landscape of C. indicum, identifying key research gaps and outlining future directions to support its evidence-based development as a therapeutic and dietary agent. Full article

Background: Oral iron supplementation or food fortification is essential for managing or preventing iron deficiency but often causes gastrointestinal side effects. While solubility has traditionally been considered a requirement for iron uptake via the DMT1 transporter, recent evidence shows that insoluble iron can also be absorbed through endocytosis, raising questions about particle size and epithelial responses. Methods: Human intestinal cell lines (Hutu-80 and Caco-2) were exposed to physiologically relevant but elevated iron levels (0.5 mM Fe, 48 h) as ferric pyrophosphate, ferrous fumarate (both prone to precipitation), and soluble ferric EDTA. Cell survival and COX-2 protein were quantified by ELISA, solubility by ICP-OES, and particle size in cell culture medium by dynamic light scattering analyses. Results: Ferric pyrophosphate (0.62–3.8 μm) markedly increased COX-2 expression in Hutu-80 cells (254% ± 37%, n = 3, p = 4.11 × 10⁻⁵) and in Caco-2 cells (78% ± 8%, n = 3, p = 0.01) compared to the control. Ferrous fumarate (237–866 nm) also induced COX-2, but only in Hutu-80 cells (62% ± 11%, n = 3, p = 0.04), whereas ferric EDTA showed no effect in either cell line. COX-2 induction was associated with larger particles in the medium (≥237 nm), whereas smaller particles (<146 nm) were not. Conclusions: Particle size appears to be a critical determinant of cell survival and iron-induced epithelial COX-2 expression. Iron compounds that present as both soluble and particulate forms may optimize bioavailability, but controlling aggregate size (<146 nm) could reduce inflammatory signaling. These findings may have important implications for cell culture systems and warrant in vivo validation in iron supplemental studies. Full article