Polysaccharides, as structurally diverse and biologically versatile natural macromolecules, have long been recognized for their indispensable roles in immune regulation, intercellular communication, and tissue architecture. Their intrinsic biocompatibility, biodegradability, and chemical modifiability position them at the interface between small-molecule drugs, biologics, and functional biomaterials. This review provides a systematic overview of the biological characteristics, historical evolution, and clinical applications of polysaccharide-based drugs, with an emphasis on marketed products and advanced clinical candidates. We critically discuss recent progress in polysaccharide-based delivery platforms, including nanoparticles, hydrogels, and polysaccharide-drug conjugates, highlighting how molecular design-such as molecular weight control, glycosidic linkage configuration, and functional group substitution-governs pharmacological activity and targeting performance. Particular attention is given to antitumor applications, where natural and chemically modified polysaccharides (e.g., selenized, phosphorylated, and sulfated derivatives) exert multitarget effects through cell cycle arrest, apoptosis induction, tumor microenvironment remodeling, and immunomodulation. Despite significant advances, challenges related to structural heterogeneity, batch-to-batch variability, and incomplete structure-activity relationship elucidation continue to hinder clinical translation. By integrating structural precision with mechanistic clarity, polysaccharide-based drugs are poised to evolve from supportive agents into rationally designed, next-generation therapeutic platforms.

Gastric acid and pepsin damage the GI tract lining in peptic ulcer disease. It affects many people worldwide, especially in developing countries. H1 antihistamines relieve allergy symptoms by blocking H1 receptors, which histamine binds. We designed novel benzimidazole-linked isoxazoline derivatives, molecular docking was carried out to study their possible target interaction with the anti-ulcer associated target 7W48 and H1 antihistaminic target 8X5Y, and synthesized 1-hydroxyethyl)-1H-benzimidazole by condensation of o-phenylenediamine with lactic acid. Claisen-Schmidt condensation of ketone derivatives with substituted aromatic aldehydes produced chalcones. Benzimidazole-linked isoxazoline derivatives (6a-6h) were produced by hydroxylamine hydrochloride cyclization. The ligands with the highest docking scores were selected for biological target evaluation (6d: -7.66 and 6e: -8.62, respectively). In ethanol-induced gastric ulcer models, compound 6d showed dose-dependent gastroprotection, with ulcer indices of 4.227 ± 0.110 (200 mg/kg) and 3.523 ± 0.095 (400 mg/kg) exhibiting 27.59% and 39.64% inhibition, respectively, but less effective than omeprazole (1.380 ± 0.046; 76.36% In an ex vivo study, compound 6e showed concentration-dependent inhibition (20.700 ± 0.990%-73.800 ± 0.849% at 200-400 mg/kg), but less than Mizolastine (80.700 ± 0.849% at 1.6 μg/ml). Compound 6d had dose-dependent antiulcer activity. The concentration-dependent anti-histaminic activity of compound 6e was significant. Standard drugs (omeprazole and mizolastine) were stronger than both compounds. These derivatives showed promising gastroprotective and antihistaminic properties and can be used as lead for further optimization and development. The combined molecular docking and biological evaluation results suggest that compounds 6d and 6e can be further explored for anti-ulcer and antihistaminic activities, respectively. Nevertheless, to confirm their suitability for further drug development studies, experimental validation of their ADME-related properties, toxicity predictions, and proposed molecular mechanisms is required.

This study aimed to investigate the protective effects of nano-formulated vitamin E combined with mesenchymal stem cell (MSC)-derived exosomes in bleomycin-induced lung fibrosis. AD-MSCs were isolated, expanded, and characterized by spindle morphology with high CD105/CD73 and low CD34/CD45 expression. Exosomes isolated from these cells displayed typical spherical morphology (131 nm), high CD81/CD63/CD9 expression, and low CD14. Skin fibrosis was induced in rats by subcutaneous administration of bleomycin. Animals subsequently received free vitamin E, nano-formulated vitamin E, or exosomes loaded with nano-formulated vitamin E. The antifibrotic efficacy of these treatments was assessed using biochemical, molecular, histopathological, and immunohistochemical analyses. Vitamin E nanoemulsion (mean of 48 nm, PDI 0.221, zeta -27.6 mV) was successfully loaded into the exosomes (EE 86.3%, LE 19.8%), yielding stable vesicles (137 nm) with excellent cytocompatibility. The formulation markedly attenuated bleomycin-induced fibrotic injury by restoring redox balance, reduction of TNF-α and TGF-β1 and attenuated extracellular matrix remodeling by decreasing collagen I, α-SMA, MMP-2, and TIMP-1. Moreover, inhibition of the NLRP3/caspase-1/GSDMD pathway and IL-1β indicated suppression of pyroptosis. VEGFR2 expression was also reduced, accompanied by marked improvement in histopathological alterations. The combination therapy exerted pronounced anti-fibrotic effects through coordinated antioxidant, anti-inflammatory, anti-pyroptotic, anti-ECM-remodeling, and anti-angiogenic mechanisms.

Gliomas are the most common and highly harmful primary central nervous system tumors. Small interfering RNA (siRNA) has been proposed as a promising therapeutic strategy for glioma by specifically silencing target gene expression. However, the instability of siRNA and its poor permeability across the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) have significantly limited its clinical application. Therefore, appropriate delivery systems are urgently required to enhance the stability and targeting efficiency of siRNA. Nano-delivery systems, due to advantages such as protecting siRNA from being degraded by enzymes, increasing the rate of drug entry into the brain, and enabling targeted delivery, have become an effective means to solve the problem of siRNA treatment for glioma. This review outlines the design strategies, types, and application progress of siRNA nano-delivery systems for glioma treatment. It focuses on how biological macromolecule-based, polymer-based, lipid-based, inorganic, and biomimetic systems overcome in vivo delivery barriers through their material properties and functional modifications. The review also covers the mechanisms by which siRNA inhibits glioma, the strategies carriers use to cross the BBB, and combination therapy approaches. It then discusses the current challenges in this field and the prospects for clinical translation.

GalNAc-modified extracellular vesicles (EVs) derived from hypoxic pancreatic cancer cells and loaded with ANXA2 siRNA were developed to modulate the immunosuppressive tumor microenvironment (TME). Characterization confirmed successful surface modification and efficient siRNA loading in EVs with a diameter of approximately 100-120 nm. In vitro, these engineered EVs inhibited pancreatic cancer cell proliferation, migration, and invasion and promoted apoptosis. Additional cargo-matched comparison showed that GalNAc-modified hypoxic EVs carrying ANXA2 siRNA produced stronger ANXA2 silencing and more pronounced anti-migratory, anti-invasive, and pro-apoptotic effects than unmodified hypoxic EVs carrying the same siRNA, whereas GalNAc modification alone did not show an obvious independent antitumor effect. In a xenograft model, treatment reduced tumor volume by approximately 50% at week 4 and prolonged median survival from 45 to 60 days. Multi-omics and immune analyses suggested suppression of the PI3K/AKT signaling pathway and remodeling of the immunosuppressive TME, as reflected by increased CD8+ T-cell infiltration, reduced tissue-associated immunoreactivity for IL-6, IL-10, and TNF-α, and increased soluble IFN-γ, IL-2, and GM-CSF levels. These findings indicate that GalNAc-modified hypoxic EVs carrying ANXA2 siRNA can inhibit tumor progression and modulate the TME in pancreatic cancer, supporting their potential as a therapeutic delivery platform.

The increasing global burden of type 2 diabetes mellitus (T2DM) and the limited efficacy of single-target therapies highlight the potential of multi-component interventions. Here, licorice flavonoids (LF), a multi-component extract from Glycyrrhiza uralensis, were evaluated for their antidiabetic effects and underlying mechanisms in T2DM. LF were prepared and chemically characterized by LC-MS-based profiling and quantitative analysis and their effects were assessed in high-fat, high-sugar diet/streptozotocin (HFD/STZ)-induced diabetic mice and sodium palmitate (SP)-induced insulin resistance (IR) HepG2 cells. LF markedly improved metabolic abnormalities in diabetic mice, as evidenced by reduced fasting glucose levels, improved glucose handling and insulin sensitivity, together with alleviation of dyslipidemia. In IR HepG2 cells, LF promoted glycogen synthesis, suppressed gluconeogenesis and lipogenesis, and enhanced fatty acid oxidation. Mechanistically, LF modulated the AMPK/mTORC1/AKT signaling network, as evidenced by increased AMPK and AKT phosphorylation and reduced mTORC1 activity. Pharmacological inhibition of AMPK with BAY-3827 partially attenuated LF-induced signaling changes, supporting a role for AMPK while suggesting the involvement of additional regulatory mechanisms. Collectively, these results support the potential of LF as a multi-component therapeutic strategy for T2DM and offer mechanistic insight into its beneficial effects on metabolic dysfunction through the AMPK/mTORC1/AKT signaling network.

Targeting both tumor cells and microenvironment is a promising anticancer strategy. FGFR1 and VEGFR2 represent important drivers of tumor progression and angiogenesis. We engineered multitarget proteins by fusing DR5‑specific TRAIL DR5-B with SRH and P9 peptides antagonizing VEGFR2 and FGFR1, respectively. SRH-DR5-B, DR5-B-P9, and SRH-DR5-B-P9 fusions demonstrated nanomolar affinity for receptors DR5, VEGFR2, and FGFR1 and reduced viability of FGFR1-positive gastric (MKN-45) and colon (HCT116, COLO 205) adenocarcinoma cells. DR5‑B-P9 and SRH‑DR5‑B‑P9 decreased phospho‑FGFR1 levels in FGF2‑stimulated NIH3T3 fibroblasts and MKN‑45 cells. In a co‑culture of MKN‑45, NIH‑3T3, and bEnd.3 cells, SRH‑DR5‑B‑P9 with gemcitabine showed greater cytotoxicity than DR5‑B. In MKN‑45 xenografts, SRH‑DR5‑B‑P9 inhibited tumor growth more efficiently and durably versus other proteins. Reduced vascular density in SRH‑DR5‑B and SRH‑DR5‑B‑P9‑treated tumors was demonstrated by CD31 immunostaining and by optoacoustic microangiography. PAS+/CD31- staining indicated suppressed vasculogenic mimicry, most pronounced with DR5‑B‑P9 and SRH‑DR5‑B‑P9. FLIM imaging revealed a glycolysis‑to‑oxidative phosphorylation shift in DR5‑B and SRH‑DR5‑B‑P9‑treated tumors, suggesting reprogrammed tumor bioenergetics. In HCT116 xenografts, SRH‑DR5‑B‑P9 suppressed tumor growth and CD31+ and PAS+/CD31- elements density more effectively than DR5‑B, confirming the results from MKN‑45 model. This supports a single‑fusion‑molecule strategy that activates DR5 while inhibiting FGFR1 and VEGFR2 for gastric and colorectal cancer therapy.

Combination therapy employing nanotechnology provides augmented efficacy over monotherapy. Spanlastics (SPs) are flexible nanovesicles that facilitate permeation across biological barriers. This study developed etodolac (ETD)-loaded SPs and atorvastatin calcium (ATR)-loaded SPs and evaluated the combined effects of ETD-SPs/ATR-SPs versus monotherapy using MCF-7 cells and a CFA-induced arthritis rat model. SPs were prepared and the effects of edge activator type and Span 60:EA ratio on in vitro characterization were evaluated. SPs were spherical, negatively charged, with particle sizes suitable for transdermal delivery. SPs dispersions showed enhanced skin permeation of ETD and ATR compared with free-drug controls. In vitro cytotoxicity studies against MCF-7 cells demonstrated concentration-dependent cytotoxic activity of ETD- and ATR-loaded SPs under the tested conditions. The combination therapy of ETD-SPs and ATR-SPs showed a lower estimated IC50 compared with the corresponding single-agent SPs formulations, evidenced by combination index lower than 1, indicating synergistic interaction at selected effect levels. In vivo anti-inflammatory assessment demonstrated that ETD-SPs and ATR-SPs combination-loaded hydrogel reduced paw thickness and modulated inflammatory biomarkers more effectively than monotherapy, with improved histological appearance. This research establishes SPs-based combination therapy as a promising delivery approach for improving cytotoxicity against MCF-7 cells and anti-inflammatory activity in CFA-induced arthritis.

Nanocarriers are commonly designed and evaluated based on their physicochemical properties, including size, morphology, surface charge, composition, ligand density, drug loading, and release behavior. After administration, however, nanocarrier surfaces are rapidly remodeled by proteins, lipids, metabolites, enzymes, mucins, salts, and immune components present in systemic, mucosal, luminal, and disease-associated biofluids, thereby generating an acquired biological identity. Rather than focusing predominantly on plasma protein coronas or individual exposure environments, this review integrates biofluid-specific biological identity across administration routes and pathological states with the dynamic evolution of hard and soft coronas and its consequences for colloidal stability, immune recognition, and therapeutic performance. A further distinguishing emphasis is the translation of these nano-bio interactions into biological-identity-by-design strategies, standardized biofluid testing, and formulation and quality-control considerations. Strategies for biological-identity-by-design, including controlled corona formation, albumin and apolipoprotein pre-coating, ligand-protein co-design, antifouling interfaces, biomimetic camouflage, and disease-fluid programming, are evaluated. Treating biological identity as a formulation and quality attribute may improve the predictability, reproducibility, safety, and clinical translation of advanced drug-delivery systems.

Diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in hepatic triglyceride (TG) synthesis, is considered a promising therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH). Small interfering RNAs (siRNAs) targeting conserved regions of human and mouse DGAT2 mRNA were designed, synthesised and screened in vitro leading to the identification of a GalNAc-conjugated siRNA, VX093L, which mediates potent DGAT2 mRNA knockdown in both human and mouse hepatocytes and exhibits sustained hepatic DGAT2 silencing in healthy mice. In a high-fat diet (HFD)-induced MASH mouse model, the effects of VX093L (1 or 3 mg/kg, biweekly) were evaluated in comparison with the approved drug resmetirom (10 mg/kg, daily). Eight weeks of treatment with VX093L potently silenced hepatic DGAT2 (>80%, p < 0.0001), thereby inhibiting hepatic TG synthesis and significantly ameliorating hepatic steatosis. Notably, VX093L treatment also effectively attenuated fibrosis, with 1 mg/kg VX093L exhibiting greater anti-fibrotic efficacy than resmetirom, without an increase in inflammation. In conclusion, VX093L represents a promising siRNA-based therapeutic for the treatment of MASH.

The rapid emergence of multidrug-resistant (MDR) bacterial infections has intensified the demand for advanced antimicrobial drug delivery strategies capable of improving therapeutic efficacy while overcoming the limitations of conventional antibiotics. Bacteriophage therapy has re-emerged as a promising antibacterial approach because of its high specificity and potent activity against antibiotic-resistant pathogens. Nevertheless, the clinical translation of free bacteriophages remains restricted by multiple biological barriers, including rapid immune clearance, limited retention at infection sites, enzymatic degradation, poor stability, and inadequate penetration into bacterial biofilms. Hydrogel-based drug delivery systems have emerged as versatile biomaterial platforms that effectively address these challenges by protecting bacteriophages from environmental degradation, enabling localized administration, prolonging residence time, and providing sustained and controlled phage release. This review critically discusses the major biological barriers limiting successful bacteriophage therapy and highlights recent advances in hydrogel engineering strategies designed to improve phage encapsulation, stability, release behavior, and antibacterial efficacy. Furthermore, the physicochemical characteristics of hydrogels that influence phage delivery, including biocompatibility, porosity, swelling behavior, degradability, tissue adhesiveness, and mechanical properties, are examined in relation to their effects on phage retention and release. Recent applications of hydrogel-assisted bacteriophage delivery in chronic wound infections, biofilm-associated infections, surgical site infections, and other MDR bacterial diseases are summarized, with particular emphasis on localized antimicrobial therapy. Finally, current challenges related to formulation design, large-scale manufacturing, regulatory approval, and clinical translation are discussed, together with future perspectives for developing clinically applicable hydrogel-based phage delivery systems. Collectively, this review evaluates the current evidence supporting hydrogel-mediated bacteriophage delivery and identifies key considerations for the development and clinical translation of effective localized phage delivery systems against multidrug-resistant bacterial infections.

Diabetes mellitus can cause progressive renal injury characterised by oxidative stress, inflammation and impaired renal function. This study investigated the kidney- and cell-protective potential of acarbose-guar gum solid dispersions (AGSDs) using in vitro and in vivo diabetic models. In BHK-21 cells, AGSD-3 showed improved biocompatibility, with higher cell viability (65.54 ± 0.41%) than acarbose (56.67 ± 0.24%) and reduced lactate dehydrogenase (LDH) release (7.29 ± 0.13%) at 100 µg/mL. Under high-glucose conditions, AGSD-3 significantly reduced lipid peroxidation and enhanced superoxide dismutase (SOD), catalase and glutathione S-transferase (GST) activities (p < 0.001). In diabetic rats, AGSD-3 (50 mg/kg) significantly improved renal function, reducing serum creatinine, urea and uric acid to 0.45 ± 0.02, 36.00 ± 0.96 and 2.00 ± 0.02 mg/dL, respectively, and normalised relative kidney weight. Histopathological findings further supported restoration of renal architecture. AGSD-3 enhanced renal antioxidant status, with increased SOD, catalase and GST activities, while reducing nitric oxide, xanthine oxidase and acetylcholinesterase (AChE) activities (p < 0.001). Furthermore, AGSD-3 reduced TNF-α and IL-6 while increasing IL-10 levels. Overall, AGSD-3 exhibited antioxidant, anti-inflammatory and renoprotective effects, supporting its potential as an improved acarbose-based formulation for diabetes-associated renal injury.

Healing of gastric ulcer (GU) can terminate the progression into more serious deteriorations. A promising and versatile vesicular nanoformulation, namely; phytosomes (PHY), was fabricated to maximise the GU healing efficacy of the naturally occurring bioactive component; melatonin (MLT). The solvent evaporation-hydration process ensnared MLT in the phytosomal complex, namely; melatonin loaded phytosomes (MLT-loaded PHY), that were fully described. A randomised full factorial design (2[3]) was applied with three independent key parameters (IKPs) at two levels. The optimal formulation, melatonin soybean phosphatidylcholine loaded chitosan coated phytosomes (MLT-SPC100 loaded/CS-coated PHY (F6)), was the most convenient one with acceptable MLT percentage entrapment efficiency (EE %, 69.467 ± 2.901%) and particle size (PS, 248.200 ± 03.830 nm) values, besides highest zeta potential (ZP, +30.267 ± 0.981 mV) one. Thereafter, it was further characterised with regard to its mucoadhesion efficiency, solid state characterisation, morphology, in vitro dissolution, physical stability, protein adsorption (opsonization) resistance, cytotoxicity, and finally in vivo healing efficacy against ethanol-induced GU in rats. Amongst the treated groups, the healing efficacy of the optimal formulation (F6) was noteworthy, as demonstrated by histological, immunohistochemical (IHC), and biochemical investigations. Hence, the aforementioned formulation deserves consideration as a promising GU remedial strategy.

Atopic dermatitis (AD) is a long-term skin disease that causes redness, itching, and a loss of skin barrier function, which sometime shows significant effect on a person's quality of life. In this study nanostructured lipid carrier (NLCs)-based hydrogel was fabricated for the topical delivery of triamcinolone acetonide (TA) with enhance therapeutic efficacy for the management of AD. TA-loaded NLCs were developed using high pressure homogeniser and characterised. The optimised NLCs composition showed a particle size of 92.06 nm, PDI of 0.324, ZP of -28.81 mV, and entrapment efficiency of 85.17%, suggesting good stability and drug incorporation. Ex vivo skin permeation studies of TA-NLCs hydrogel demonstrated sustained drug permeation of 79.86% at 8 h, significantly higher, compared to pure drug incorporated hydrogel (p < 0.05). Skin irritation studies verified the safety of the formulation with no significant signs of edoema and erythema. The anti-inflammatory effect was assessed using a carrageenan-induced rat paw edoema-based assay showed that the TA-NLCs hydrogel had higher inhibition of edoema than the marketed corticosteroid cream. Thus, the developed TA-NLCs hydrogel showed enhanced anti-inflammatory efficacy and sustained drug permeation, suggests that the developed TA-NLCs hydrogel could be an efficacious topical delivery system for the management of AD.