Search Results (1,236)

The body’s microbiota plays a fundamental role in maintaining homeostasis and influences immune function, metabolism, and tissue integrity. A growing body of research suggests that fluctuations in the composition and abundance of individual microbiota populations may influence cancer development and the effectiveness of therapy. The condition of microbiota dysbiosis has been demonstrated to induce chronic inflammation, immune system dysregulation, and, most significantly, modulation of molecular pathways that promote tumorigenesis. The efficacy and toxicity of cancer treatment can be influenced by the composition of the microbiota. Bacteria can modify the effectiveness and toxicity of chemotherapy and immunotherapy by affecting drug metabolism and the body’s immune response. In contrast, the development of anticancer therapies that utilize bacteria is gaining increasing interest. This alternative to conventional treatment utilizes the natural ability of certain bacterial species to selectively colonize hypoxic and necrotic environments. The exploration of natural and genetically modified bacteria as vectors for the delivery of cytotoxins, immunomodulators, or therapeutic genes in the combat of cancer is a current area of research. In addition, their capacity to stimulate an antitumor immune response is also exploited. Preclinical investigations in animals have demonstrated the efficacy of this therapeutic approach, underscoring the promise of bacterial therapies as either an adjunct to conventional treatment or as a standalone strategy for combating cancer. This article synthesizes the current knowledge regarding the role of microbiota in carcinogenesis in animals and discusses recent developments in the field of bacterial therapies. The text also addresses the challenges, safety considerations, and future perspectives associated with translating microbiota-targeted and bacterial therapies into veterinary and comparative oncology. Full article

Background: Glioblastoma (GBM) remains a lethal malignancy due to temozolomide (TMZ) resistance and limited drug penetration across the blood–brain barrier, largely driven by hyperactive DNA damage repair mechanisms such as poly (ADP-ribose) polymerase (PARP). To address these challenges, we developed folic acid-targeted PLGA–zein hybrid core–shell nanoparticles for the codelivery of the alkylating agent TMZ and the natural PARP inhibitor Ellagic acid (FA-TMZ/EA-PZ-CS NPs), thereby enabling simultaneous enhancement of drug delivery and suppression of chemoresistance pathways. Methods and Results: The dual-drug nanoplatform was fabricated using a double-emulsion solvent evaporation method and functionalized via EDC/NHS-mediated folic acid conjugation to promote receptor-mediated uptake. Physicochemical characterisation confirmed uniform spherical morphology, high colloidal stability, efficient drug encapsulation, and sustained biphasic drug release consistent with a core–shell diffusion mechanism. In LN229 glioblastoma cells, folic acid conjugation significantly enhanced cellular internalisation and cytotoxic efficacy compared to free drugs and non-targeted nanoparticles. Combination index analysis revealed strong synergism between TMZ and ellagic acid, resulting in markedly reduced IC₅₀ values. Mechanistic studies demonstrated apoptosis induction, increased DNA damage, inhibition of cell migration at sub-cytotoxic concentrations, and downregulation of PARP gene expression. Conclusion: Overall, this study establishes a targeted core–shell nanotherapeutic strategy that integrates chemotherapy with DNA repair inhibition to overcome TMZ resistance, offering a mechanistically sound strategy that serves as a foundational framework for future translational research. Full article

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a significant pathogen for both hospital-acquired and community-acquired infections, characterized by its strong epidemic potential and high mortality rate, posing a severe threat to global public health. CRKP spreads widely across the globe through the horizontal transfer of plasmid-mediated resistance genes such as *blaKPC*, *blaNDM*, and *blaOXA-48*. The clinical treatment options for this bacterium are limited, and its resistance has been increasing year by year, urgently necessitating the development of new antimicrobial drugs or alternative strategies. In recent years, the CRISPR-Cas system has shown great potential in the diagnosis and treatment of CRKP, including rapid detection and identification, gene editing, antimicrobial strategies, and resistance inhibition. For instance, CRISPR-Cas12a/13a can be used for the rapid detection and identification of CRKP, while CRISPR-Cas9/Cas3 can target resistance genes to reverse the resistance of strains. With the advancement of delivery and biotechnologies, the CRISPR-Cas system is expected to become an important tool against drug-resistant CRKP. This review focuses on the application of the CRISPR-Cas system in the detection and treatment of CRKP, analyzing its technical advantages, limitations, and future development directions. Full article

Breast cancer remains a leading cause of cancer-related mortality worldwide, with treatment resistance, recurrence, and metastasis significantly limiting the effectiveness of conventional therapies. Photodynamic therapy (PDT) has emerged as a minimally invasive and highly selective approach, utilizing photosensitizer-generated reactive oxygen species (ROS) to achieve precise tumor cytotoxicity while preserving surrounding healthy tissue. However, clinical translation of PDT remains constrained by critical biological barriers within the tumor microenvironment, including tumor hypoxia, limited light penetration, poor photosensitizer stability, and inefficient cellular uptake. Antigen-targeted liposomal nanocarriers offer a compelling solution by enabling targeted drug delivery and tumor-specific photosensitizer accumulation, prolonged systemic circulation, and enhanced cellular internalization. Their multifunctional architecture uniquely supports combinational therapeutic strategies, integrating PDT with chemotherapy, photothermal therapy, gene therapy, X-ray-induced photodynamic therapy (X-PDT) and immune checkpoint blockade, thereby amplifying antitumor efficacy and overcoming drug resistance mechanisms. This review comprehensively summarizes recent advances in liposome-based PDT for breast cancer, highlighting multimodal therapeutic integration. Special emphasis is placed on preclinical and emerging clinical outcomes, pilot-scale manufacturing considerations, and strategies to minimize immune clearance. Full article

Targeted drug delivery remains difficult because multiple biological barriers interfere with the stable transport of therapeutics to the site of action. Polymeric nanocarriers have gained broad attention as delivery platforms since their composition and surface properties can be adjusted to improve circulation behavior and cellular delivery. This review discusses the major biological barriers involved in targeted drug delivery and describes how polymeric nanocarriers are engineered to overcome them. Major carrier types, including polymeric nanoparticles and micelles, are considered with emphasis on their physicochemical and interfacial features. Particular attention is given to surface engineering and stimuli-responsive design as key strategies for barrier transport and controlled cargo release. The review also highlights representative applications in anticancer, gene, protein, and vaccine delivery, together with translational issues such as biocompatibility, stability, reproducibility, scale-up, and regulatory acceptance. Full article

Amphiphilic statistical copolymers are valuable synthetic macromolecules for the formation of small, well-defined nanoassemblies able to be utilized as nanocarriers for drug and/or gene delivery applications. In this work, the synthesis of amphiphilic linear statistical copolymers of the poly(benzyl methacrylate-co-dimethylaminoethyl methacrylate) [P(BzMA-co-DMAEMA)] type is described in three different comonomer compositions. Their synthesis was realized through a one-pot reversible addition-fragmentation chain transfer (RAFT) solution polymerization scheme. Further quaternization of the amine groups of DMAEMA with methyl iodide (CH₃I) resulted in cationic amphiphilic statistical copolymers. Macromolecular characterization was performed using size exclusion chromatography (SEC) and spectroscopic techniques (¹H-NMR and ATR-FTIR). The aggregation properties of the copolymers in aqueous media were studied via dynamic light scattering (DLS) and electrophoretic light scattering (ELS). Bimodal size distributions were determined in some cases. The BzMA to DMAEMA ratio determined aggregate size, with the copolymer of lower hydrophobic BzMA content producing smaller nanoparticles. Cryogenic transmission electron microscopy (cryo-TEM) showed the presence of spherical assemblies resulting from aggregation of primary micelles in the case of higher BzMA content. The copolymer aggregates experience dissociation at high salt concentration, and the pH-responsiveness of the amine precursors results in the formation of multifunctional potential nanocarriers. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial–ROS–inflammatory signaling, aggregation–proteostasis failure, synaptic–neuroimmune dysfunction, and gut–brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP–AMP synthase (cGAS)—stimulator of interferon genes (STING) pathways—play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood–brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles. Full article

Carbon dots (CDs), including carbon quantum dots (CQDs), are ultra-small carbon-based nanomaterials, typically below 10 nm, with tunable photoluminescence, high aqueous dispersibility, favorable biocompatibility, low toxicity, and abundant surface functional groups. These properties make CDs promising multifunctional platforms for nanomedicine, particularly in bioimaging, biosensing, targeted drug/gene delivery, photodynamic therapy (PDT), photothermal therapy (PTT), antimicrobial treatment, and theranostic applications. This review critically examines recent advances in CD fabrication, including top-down, bottom-up, green biomass-derived, microwave-assisted, hydrothermal, and emerging hybrid strategies, with emphasis on how precursor selection, heteroatom doping, surface passivation, and polymer/ligand functionalization regulate optical performance, biological interaction, and therapeutic efficiency. The review discusses structural classification, including CQDs, graphene quantum dots (GQDs), carbon nanodots, and carbonized polymer dots (CPDs), together with major characterization approaches such as ultraviolet–visible (UV–Vis) spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and high-resolution transmission electron microscopy (HRTEM). Particular attention is given to red/near-infrared (NIR) emission, renal clearance, drug-loading behavior, reactive oxygen species (ROS) generation, toxicity mechanisms, biodistribution, and long-term biosafety. This review also highlights key translational barriers, including batch-to-batch variability, limited standardization, scalable manufacturing, regulatory uncertainty, and incomplete pharmacokinetic evaluation. It considers artificial intelligence (AI) and machine learning (ML) as emerging tools for reproducible CD design. CDs represent versatile and clinically promising nanoplatforms, but their translation requires standardized synthesis, rigorous safety assessment, and application-specific regulatory validation. Full article

Background/Objectives: With the ongoing efforts in supporting the discovery of novel targeted drug delivery systems for the upper region of the female reproductive tract (FRT), it is imperative to understand the local drug disposition pathways. We aim to obtain a comprehensive profile of the drug transporters and drug-metabolizing enzymes in the human ectocervix, uterus, and fallopian tubes, as these factors may substantially influence mucosal penetration, tissue exposure, drug disposition, and the risk of drug–drug interactions. Methods: Gene expression of 12 drug transporters and 21 drug-metabolizing enzymes was quantified using RT-qPCR. Protein expression of highly expressed transporters was assessed using immunohistochemistry (IHC). Results: Among the 12 transporters analyzed, the efflux transporters P-gp, BCRP, and MRP4 exhibited the highest expression across the ectocervix, endometrium, myometrium, and fallopian tubes, with P-gp consistently showing the greatest abundance in all evaluated FRT tissues. Expression of these transporters was significantly higher (6–17×) in myometrium compared with ectocervix. IHC demonstrated strong localization of P-gp, BCRP, and MRP4 to epithelial layers facing the lumen, as well as to stromal and vascular endothelial cells. For drug-metabolizing enzymes, all 21 phase I and II enzymes were detectable across the FRT, and 15 were expressed at comparatively higher levels across all tissue types. These included CYP1A1, CYP1B1, CYP2B6, CYP2C8, CYP2C19, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A7, UGT1A8, UGT1A10, UGT2B4, UGT2B15, and UGT2B17. Conclusions: The gene expression and localization data obtained from this work may improve our understanding of drug disposition in the FRT, which will inform selection, design, and optimization of drugs intended for targeted delivery within the FRT. Full article

Manganese-based nanomaterials have been novel multifunctional platforms in tumor immunotherapy because of their tunable multivalent states, biocompatibility, and multi-stimulus responsiveness. Current cancer treatments are insufficient and cause severe side effects; therefore, manganese-based nanomaterials are proposed in combination with immunotherapy to mitigate adverse effects. This review outlines the antitumor effects mediated by four key mechanisms: (1) activation of the cGAS-STING immune signaling pathway, (2) direct activation of immune cells, (3) induction of immunogenic cell death (ICD), and (4) modulation of the tumor microenvironment. These approaches are broadly categorized into two types: monotherapy and multimodal combination therapy. Monotherapy encompasses three specific modalities: (1) direct use as a Stimulator of Interferon Genes (STING) agonist, (2) vector-mediated targeted drug delivery, and (3) mediation of chemodynamic therapy to generate reactive oxygen species, thereby inducing ICD. Multimodal combination therapy involves synergistic integration with traditional or emerging treatment modalities, including chemotherapy, radiotherapy, photodynamic therapy, sonodynamic therapy, and low-level light therapy, as well as multimodal combination treatment methods. It significantly enhances the antitumor efficacy of traditional therapies through immunostimulation, thus achieving synergistic breakthroughs in treatment efficiency and survival rate. Collectively, the multifunctional integration of manganese-based materials is a novel strategy for developing “self-adjuvant” immunotherapeutic platforms and investigating the clinical translation potential. Full article

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality worldwide, primarily due to the systemic toxicity and drug resistance associated with conventional doxorubicin (DOX) therapy. To overcome these limitations, we developed and optimized a novel cationic-ionizable lipid nanoparticle platform, QTPlus, for the co-delivery of DOX and siRNA targeting fibroblast growth factor 2 (siFGF2). Methods: The study evaluated the physicochemical properties, cellular uptake, gene regulation, apoptosis induction, and in vivo antitumor efficacy and safety of QTPlus-DOX-siFGF2 in breast cancer models. Results: QTPlus nanoparticles based on the A-066 formulation achieved uniform particle size (~218 nm), low polydispersity (PDI 0.164–0.214), and high encapsulation efficiencies (DOX: 49.56 ± 0.15%; siFGF2: 77.66 ± 1.30%). In vitro release studies revealed a robust pH-responsive profile, characterized by sustained stability at physiological pH (7.4) and rapid burst release at acidic endosomal pH (5.5). In MCF-7 and MDA-MB-231 cells, QTPlus-DOX-siFGF2 significantly enhanced cellular uptake, downregulated FGF2 (0.639-fold) and VIM (0.373-fold), and upregulated CASP3 (3.364-fold in siFGF2 group) and BRCA1 (4.041-fold). Flow cytometry showed markedly increased apoptosis (78.5% vs. 42.65% for QTPlus-DOX alone). In the MDA-MB-231 xenograft model, QTPlus-DOX-siFGF2 achieved 65.87% tumor growth inhibition with stable body weights and favorable trends in cardiotoxic biomarkers. Conclusions: These results demonstrate that QTPlus enables effective co-delivery of DOX and siFGF2, producing synergistic antitumor effects through apoptosis induction and suppression of epithelial–mesenchymal transition while improving the safety profile. QTPlus-DOX-siFGF2 represents a promising nanotherapeutic strategy for breast cancer warranting further clinical development. Full article

Intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) remains the main strategy to prevent malaria in pregnancy. However, continued drug pressure may also contribute to the emergence of resistant parasites and impact the gametocyte carriage and subsequent infectiousness. Pregnant women are thought to be a potential reservoir for malaria transmission due to the increased carriage of gametocytes following long-lasting infections. We used molecular methods to examine 100 Plasmodium falciparum (P. falciparum) isolates collected from Mozambican women at delivery in 2014-15 to determine sulfadoxine-pyrimethamine (SP) resistance polymorphisms in P. falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthetase (pfdhps) genes, as well as the presence of gametocytes by RT-qPCR. Overall, 54% and 7% of parasites harbored quintuple and sextuple pfdhfr/pfdhps mutant haplotypes, respectively. Gametocytes were detected in 34% of isolates. Gametocyte carriage was significantly associated with quintuple mutant infections (AOR = 7.5, p = 0.001), which accounted for 80% of infections with detectable gametocytes. Results indicate the relevance of ongoing surveillance of SP resistance in Mozambique to guide future evaluation of alternative intermittent preventive treatment in pregnancy (IPTp) approaches as resistance levels evolve and anticipate potential implications for parasite transmission and maternal–fetal health. Full article

The combination of thiopurine and methotrexate (MTX) is a standard co-therapy regimen for acute lymphoblastic leukemia (ALL). Despite its efficacy, this regimen is constrained by a narrow therapeutic window and considerable inter-individual variability, which heightens the risk of drug-induced liver injury (DILI). MTX-induced metabolic strain further destabilizes cytokine-sensitive thiopurine detoxification pathways during systemic inflammation. Conventional pharmacogenetic (PGx) testing for TPMT and NUDT15 variants is effective in predicting myelosuppression, but often fails to detect hepatotoxicity as an adverse effect, suggesting a clinically significant genotype-phenotype difference. This review examines the molecular determinants of DILI, emphasizing the role of secondary metabolic pathways and transporter dynamics as key modulators of risk. The study describes cytokine-mediated (IL-6, TNF-α) transcriptional suppression of cytochrome P450 enzymes and hepatic transporters (SLCO1B1, ABCC2/4) not merely as secondary modulators, but as the primary determinants of localized, tissue-specific drug exposure through disrupted nuclear receptor signaling (PXR, CAR, HNF4α). This mechanism promotes functional phenoconversion and toxic molecular shunting, leading to increased intrahepatic drug exposure. It synthesizes the current knowledge on the metabolism of thiopurine and MTX, focusing on the genetic and non-genetic factors influencing toxicity and their interactions. The review also critically evaluates the limitations of static PGx-guided dosing. It highlights the need for comprehensive, real-time risk assessment that integrates gene-environment interactions, multi-omics data, and clinical monitoring to improve precision therapy for ALL. This approach combines extended PGx profiling, transcriptomic monitoring, and clinical biomarker assessment to provide a transformative strategy for precision drug delivery. Full article

Medulloblastoma (MB) is the most frequent brain malignancy in children, frequently driven by deregulated Sonic Hedgehog (SHH) signaling. We previously identified the antidiabetic drug phenformin (Phen) as a potent Gli1 inhibitor that suppresses SHH-subtype MB growth. Despite its efficacy, systemic administration of Phen is limited by its potential to induce lactic acidosis, primarily through the suppression of hepatic gluconeogenesis. Here, we provide proof-of-concept that phospholipid (liposomes) and non-phospholipid (niosomes) vesicles (<200 nm) can be used to deliver phenformin selectively. Our results show that these vesicle-based delivery systems efficiently entrap Phen (around 50%) and release it into SHH MB cells, reducing proliferation and activating energy stress responses at higher doses. Furthermore, treated cells exhibit marked downregulation of SHH target genes Gli1 and Ptch1. In vivo, phenformin-loaded nanocarriers selectively increased drug accumulation in cerebellar tumors while minimizing systemic and hepatic exposure. Notably, niosomes demonstrated superior brain tumor targeting compared to free drug or liposome administration, as reflected by higher intratumoral concentrations of Phen compared to free drug or liposome administration. Consistent with this targeted delivery, we observed a substantial decline in intratumoral Gli1 and Ptch1 expression, confirming effective SHH pathway modulation. Together, these findings propose a promising nanotechnology-based method to improve phenformin therapeutic index in SHH MB by enhancing tumor specificity and reducing systemic toxicity. Full article

Background/Objectives: Overexpression of transferrin receptor (TFR1) is common in cancer and may be associated with inferior treatment outcomes. Due to these patterns and TFR1’s essential role in iron metabolism, the protein has been targeted for cytotoxic drug delivery. More recently, increased TFR1 expression has been linked to tumor microenvironment (TME) infiltration by immune effectors in selected tumors, but a comprehensive assessment of the genomic landscape associated TFRC (the gene encoding TFR1) expression has not been conducted. Methods: By utilizing a pan-cancer database of 93,248 patients with whole-exome and whole-transcriptome sequencing, we assessed TFRC-associated multiomic patterns. Results: We found that high TFRC expression correlates with significantly worse overall survival in multiple common solid tumor types, a higher tumor mutational burden (TMB), an increase in infiltrating effector cells with upregulated immune checkpoint markers within the TME, and increased frequency of specific high-risk genomic alterations. Further assessment in cell line models revealed increased susceptibility to cytotoxic T cells when iron metabolism is elevated, despite upregulation of the checkpoint ligand PD-L1. Conclusions: High TFRC expression, therefore, indicates worse clinical risk across multiple common tumor types but potentially increased susceptibility to cytotoxic immune effectors, informing the development of TFR1 biomarker-driven therapeutic strategies. Full article