Search Results (1,384)

Colorectal carcinoma (CRC) is characterized by mutations in p53 and the Wnt signaling pathway, and immunotherapy has shown limited efficacy in microsatellite-stable CRC. Here, CEABP1, a binding protein for the CRC biomarker carcinoembryonic antigen (CEA), was designed de novo through the AI-based computational generation methods RFDiffusion/ProteinMPNN and stringent in silico selection, for targeted delivery of purified p53 protein and transcription factor T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) transcription factor decoy (TFD) DNA into CRC cells. The cell-penetrating peptide (CPP) p28 was employed to deliver the p28-p53-CEABP1 protein, which significantly enhanced p53’s inhibition of CRC cell proliferation and xenograft tumor growth. Codelivery of the p14ARF protein together with p53 prolonged the effective antitumor duration of p53. In addition, the DNA binding domain of Max was fused with CPP and CEABP1 to deliver TCF/LEF TFD DNA, comprising concatenated consensus binding motifs for TCF/LEF and Max, into CRC cells to inhibit Wnt target gene transcription, leading to marked suppression of CRC cell proliferation and xenograft tumor growth. These findings paved the way for the development of precision anticancer therapeutics using designed binding proteins of tumor biomarkers for targeted delivery of tumor suppressor proteins and TFD DNA. Full article

Acquired Immunodeficiency Syndrome (AIDS) is caused by Human Immunodeficiency Virus (HIV), and continues to be responsible for a substantial number of deaths worldwide each year. Development of a robust and efficient HIV-1 vaccine remains a critical priority. Structural analysis of viral proteins provides a foundational approach to designing peptide-based immunogenic vaccines. In the current experiment, we used computational prediction approaches alongside molecular docking and molecular dynamics (MD) simulations to identify potential epitopes within gp120 and Nef proteins. The selected co-epitopes were fused with the HBsAg-binding protein (SBP), a 344-amino acid protein previously identified in our laboratory through screening of a human liver cDNA expression library against HBsAg, to facilitate efficient delivery to and uptake by dendritic cells (DCs), thereby enhancing antigen (Ag) presentation. Flexible linkers are used to connect B cells, Helper T Lymphocytes (HTLs), and Cytotoxic T Lymphocytes (CTLs) in a sequential manner. The assembled vaccine construct comprises 757 amino acids, corresponding to a recombinant protein of 83.64 kDa molecular weight. Structural analysis through docking studies, MD simulations, and 3D structure validation revealed that the designed protein exhibits high structural stability and potential for interaction with Toll-like receptors (TLRs). These findings support the vaccine’s ability to enhance cellular and humoral feedback, including the stimulation of T and B cells and induction of antibody (Ab) production. The results underscore the promise of this in silico designed co-epitope vaccine as a viable candidate for HIV-1 prevention and suggest that such constructs may serve as effective immunogens in future HIV-1 vaccine strategies. Full article

Pasteurella multocida is a Gram-negative bacterium causing significant livestock diseases, like fowl cholera and hemorrhagic septicemia in cattle, and wound infection in humans. Classified into four subspecies and five capsular serotypes, it possesses multiple virulence factors, including capsular polysaccharides (CPSs), lipopolysaccharides (LPSs), outer membrane proteins (OMPs), iron acquisition proteins, and toxins that serve as vaccine targets. Antimicrobial treatment is challenging, so vaccination is key. Commercial vaccines include killed and live attenuated types, which are commonly used, though they have intrinsic problems. Advanced vaccines like recombinant subunit and DNA vaccines are emerging. Subunit vaccines targeting OMPs (OmpH, OmpA, PlpE, VacJ, and PmSLP) and recombinant Pasteurella multocida toxin (rPMT) show high efficacy in animal models, and their recombinant proteins induce strong immune responses. DNA vaccines have promise but limited use. The challenges in vaccine development are the strain diversity, short-term immunity, and inconsistent cross-protection. There is also a lack of research on recombinant and subunit vaccine development for small ruminants. Future research should focus on multivalent vaccines, optimization, including improving adjuvants and optimizing DNA vaccine delivery. Full article

Cellular senescence, a state of stable cell cycle arrest accompanied by a complex senescence-associated secretory phenotype (SASP), is a fundamental biological process implicated as a key driver of lung aging and lung age-related diseases (LARDs). This review provides a comprehensive overview of the rapidly evolving field of senotyping based on cellular heterogeneity in lung development and aging in health and disease. It also delves into the molecular mechanisms driving senescence and SASP production, highlighting pathways such as p53/p21, p16^INK4a/RB, mTOR, and p38 MAPK as therapeutic targets. The involvement of various novel SASP proteins, such as GDP15, cytokines/chemokines, growth factors, and DNA damage response proteins. We further highlight the effectiveness of senotherapeutics in mitigating the detrimental effects of senescent cell (SnC) accumulation within the lungs. It also outlines two main therapeutic approaches: senolytics, which selectively trigger apoptosis in SnCs, and senomorphics (also known as senostatics), which mitigate the detrimental effects of the SASP without necessarily removing the senescent cells. Various classes of senolytic and senomorphic drugs are currently in clinical trials including natural products (e.g., quercetin, fisetin, resveratrol) and repurposed drugs (e.g., dasatinib, navitoclax, metformin, rapamycin) that has demonstrated therapeutic promise in improving tissue function, alleviating LARDs, and extending health span. We discuss the future of these strategies in lung research and further elaborate upon the usability of novel approaches including HSP90 inhibitors, senolytic CAR-T cells, Antibody drug conjugate and galactose-modified prodrugs in influencing the field of personalized medicine in future. Overall, this comprehensive review highlights the progress made so far and the challenges faced in the field of cellular senescence including SnC heterogeneity, states of senescence, senotyping, immunosenescence, drug delivery, target specificity, long-term safety, and the need for robust cell-based biomarkers. Future perspectives, such as advanced delivery systems, and combination therapies, are considered critical for translating the potential of senotherapeutics into effective clinical applications for age-related pulmonary diseases/conditions. Full article

Background/Objectives: Antibiotic resistance is a major public health concern, with considerable socio-economic consequences. Researchers are exploring alternative strategies, including nanotechnology, which has shown significance in targeted drug delivery. This study evaluates the synergistic antibacterial activity of azithromycin-loaded chitosan nanoparticles (AZM-CSNPs) against azithromycin-resistant clinical respiratory isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Klebsiella pneumoniae (K. pneumoniae). Methods: A total of 87 sputum samples (n = 87) were collected and analyzed. The ermB gene for K. pneumoniae and the ermA gene for MRSA were used to confirm resistant isolates. Among 87 samples, 29 manifested K. pneumoniae, and 32 exhibited MRSA-positive cultures, confirmed through phenotypic and genotypic methods. The RT-PCR is performed by using a cDNA Kit to determine the gene expression. Results: The results elucidate resistance of K. pneumoniae against several antibiotics, including azithromycin (15 µg), chloramphenicol (30 µg), and amoxicillin (30 µg), while MRSA also showed resistance to cefoxitin (30 µg), azithromycin (15 µg), and gentamycin (10 µg). Reduction in the MIC value of the nanoparticle formulation showed their effectiveness. The AZM-CSNPs combined with cetirizine dihydrochloride helped to down-regulate the resistant genes. Conclusions: Notably, a strong synergistic effect was observed with AZM-CSNPs in combination with cetirizine, significantly enhancing antibacterial efficacy against resistant isolates. Full article

Pulmonary fibrosis (PF) is a progressive and fatal lung disease characterized by irreversible alveolar destruction and pathological extracellular matrix (ECM) deposition. Currently approved agents (pirfenidone and nintedanib) slow functional decline but do not reverse established fibrosis or restore functional alveoli. Multifunctional bioscaffolds present a promising therapeutic strategy through targeted modulation of critical cellular processes, including proliferation, migration, and differentiation. This review synthesizes recent advances in scaffold-based interventions for PF, with a focus on their dual mechano-epigenetic regulatory functions. We delineate how scaffold properties (elastic modulus, stiffness gradients, dynamic mechanical cues) direct cell fate decisions via mechanotransduction pathways, exemplified by focal adhesion–cytoskeleton coupling. Critically, we highlight how pathological mechanical inputs establish and perpetuate self-reinforcing epigenetic barriers to regeneration through aberrant chromatin states. Furthermore, we examine scaffolds as platforms for precision epigenetic drug delivery, particularly controlled release of inhibitors targeting DNA methyltransferases (DNMTi) and histone deacetylases (HDACi) to disrupt this mechano-reinforced barrier. Evidence from PF murine models and ex vivo lung slice cultures demonstrate scaffold-mediated remodeling of the fibrotic niche, with key studies reporting substantial reductions in collagen deposition and significant increases in alveolar epithelial cell markers following intervention. These quantitative outcomes highlight enhanced alveolar epithelial plasticity and upregulating antifibrotic gene networks. Emerging integration of stimuli-responsive biomaterials, CRISPR/dCas9-based epigenetic editors, and AI-driven design to enhance scaffold functionality is discussed. Collectively, multifunctional bioscaffolds hold significant potential for clinical translation by uniquely co-targeting mechanotransduction and epigenetic reprogramming. Future work will need to resolve persistent challenges, including the erasure of pathological mechanical memory and precise spatiotemporal control of epigenetic modifiers in vivo, to unlock their full therapeutic potential. Full article

Overcoming immune resistance remains the critical barrier to durable immunotherapy responses. Tumors with non-inflamed, “cold” microenvironments exclude cytotoxic lymphocytes and evade checkpoint blockade. Innate nucleic acid-sensing pathways—including TLRs, RIG-I-like RNA sensors, and the cGAS–STING DNA-sensing axis—can recondition this hostile landscape by licensing dendritic cells, restoring antigen presentation, and recruiting effector T and NK cells. In this review, we synthesize mechanistic insights into how these receptors function across tumor and immune compartments and evaluate recent translational advances spanning small-molecule and nucleic acid agonists, engineered delivery systems, and clinical trials. We highlight challenges that have limited clinical impact, including pathway silencing, systemic toxicity, and lack of predictive biomarkers, while emphasizing emerging solutions such as tumor-intrinsic targeting, CAR-T/NK engineering, and biomarker-guided patient selection. By integrating innate activation into rational combination regimens, innate immune reprogramming offers a blueprint to convert resistant disease into one susceptible to durable immune control. Full article

Biomolecule-driven smart materials represent a paradigm shift in pharmacology, transitioning drug delivery from a passive process to an active, programmable, and highly specific intervention. These systems, constructed from or functionalized with biological macromolecules such as nucleic acids, peptides, proteins, and polysaccharides, are engineered to sense and respond to specific pathophysiological cues or external triggers. This review provides a comprehensive analysis of this rapidly evolving field. We first delineate the fundamental principles of stimuli-responsive actuation, categorizing systems based on their response to endogenous (pH, redox, enzymes, ROS) and exogenous (temperature, light, magnetic fields) triggers. We then conduct an in-depth survey of the primary biomolecular architectures, examining the unique design space offered by DNA nanotechnology, the functional versatility of peptides and proteins, and the biocompatibility of polysaccharides. Key therapeutic applications in oncology, inflammatory diseases, and gene therapy are discussed, highlighting how these intelligent systems are being designed to overcome critical biological barriers and enhance therapeutic efficacy. Finally, we address the formidable challenges—spanning biocompatibility, manufacturing scalability, and regulatory navigation—that constitute the “bench-to-bedside” chasm. We conclude by exploring future perspectives, including the development of multi-stimuli responsive, logic-gated systems and the transformative potential of artificial intelligence in designing the next generation of personalized nanomedicines. Full article

Nucleic acid aptamers are single-stranded DNA or RNA molecules that can bind to a target with high specificity and affinity, as screened by the Systematic Evolution of Ligands by Exponential Enrichment (SELEX). In recent years, SELEX technologies have been significantly advanced for the screening of aptamers for a variety of target molecules, cells, and even bacteria and viruses. By integrating recent advances of emerging technologies with SELEX, novel screening technologies for nucleic acid aptamers have emerged with improved screening efficiency, reduced production costs and enhanced aptamer performance for a wide range of applications in medical diagnostics, drug delivery, and environmental monitoring. Aptasensors utilize aptamers to detect a wide range of analytes, allowing for the accurate identification and determination of small molecules, proteins, and even whole cells with remarkable specificity and sensitivity. Further optimization of the aptasensor can be achieved by aptamer truncation, which not only maintains the high specificity and affinity of the aptamer binding with the target analytes, but also reduces the manufacturing cost. Predictive models also demonstrate the powerful capability of determination of the minimal functional sequences by simulation of aptamer–target interaction processes, thus effectively shortening the aptamer screening procedure and reducing the production costs. This paper summarizes the research progress of protein-targeted aptamer screening in recent years, introduces several typical aptasensors at present, discusses the optimization methods of aptasensors by combining efficient SELEX with advanced predictive algorithms or post-SELEX processes, as well as the challenges and opportunities faced by aptasensors. Full article

Extracellular vesicles (EVs) are rapidly gaining recognition as critical mediators of inter-cellular communication during viral infections. To contribute to fill the gap in knowledge regarding the role of EVs in adenovirus infection, we used human adenovirus type 4 of species Mastadenovirus exoticum (HAdV-E4), a prevalent respiratory and ocular pathogen, and characterized the cargo and biological properties of EVs released by HAdV-E4-infected A549 lung epithelial cells at a pre-lytic stage of infection. Using immunocapture-based isolation and multi-omics approaches, we found that infection profoundly alters the EV uploaded proteome and small non-coding RNA repertoire. Mass spectrometry identified 268 proteins unique to EVs purified from infected cells (AdV-EVs), with enrichment in pathways supporting vesicle trafficking and viral protein translation, and importantly also a few virus-encoded proteins. A small RNA transcriptome analysis showed differential uploading in AdV-EVs of various small non-coding RNAs, including snoRNAs, as well as the presence of virus associated RNAs I and II. Notably, AdV-EVs contained viral genomic DNA and could initiate productive infection upon delivery to naïve cells in the absence of detectable viral particles. Our data suggest that EVs released during the HAdV-E4 infection may serve as vehicles for non-lytic viral dissemination and highlight their possible role in intra-host dissemination Full article

Proton therapy enables precise dose delivery to tumors while sparing healthy tissues, offering significant advantages over conventional radiotherapy. Accurate prediction of biological doses requires detailed knowledge of radiation interactions with biological targets, especially DNA, a key site of radiation-induced damage. While most biophysical models (LEM, mMKM, NanOx) rely on water as a surrogate, this simplification neglects the complexity of real biomolecules. In this work, we calculate the stopping power and range of protons in liquid water, dry DNA, and hydrated DNA using semi-empirical cross sections for ionization, electronic excitation, electron capture, and electron loss by protons and neutral hydrogen in the 10 keV–100 MeV energy range. Additionally, ionization cross sections for uracil are computed to explore potential differences between DNA and RNA damage. Our results show excellent agreement with experimental and ab initio data, highlighting significant deviations in stopping power and range between water and DNA. Notably, the stopping power of DNA exceeds that of water at most energies, reducing proton ranges in dry and hydrated DNA by up to 20% and 26%, respectively. These findings provide improved input for Monte Carlo simulations and biophysical models, enhancing RBE predictions and dose accuracy in hadrontherapy. Full article

Tuberculosis (TB), primarily caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of infectious disease mortality worldwide. Global TB control efforts face several hurdles, including the lack of a broadly effective vaccine, limited sensitivity of current diagnostics, particularly for paucibacillary and extrapulmonary TB, and significant adverse effects associated with prolonged small-molecule drug regimens. The growing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains further underscores the urgent need for innovative therapeutic strategies. We outline characteristics of next-generation TB therapeutics. We show that antibody (Ab)-drug conjugates (ADCs) satisfy many of those desirable characteristics. Since a major hurdle to this approach lies in Mtb-specific Abs, we highlight an open-access resource comprising a broad panel of Mtb-specific mouse monoclonal antibodies targeting key factors involved in Mtb survival, immune evasion, and pathogenesis. These critical Mtb virulence factors include heat shock proteins (GroES, DnaK, and HspX), surface-associated or secreted proteins (LAM, Ag85, HBHA, Mpt64/CFP-21, and PhoS1/PstS1), cell wall/envelope-associated proteins (LprG/p27), and detoxifying enzymes (KatG and SodA). The resource provides full-length sequences of the immunoglobulin variable regions, enabling antibody engineering and facilitating translational TB research across vaccine design, diagnostic development, and immunotherapeutic applications, in addition to ADCs. This ADC targeted delivery strategy holds promise for overcoming TB heterogeneity and eliminating both active and dormant Mtb populations within a single therapeutic formulation and offers a novel avenue for precision TB treatment. Full article

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, associated with a high tendency for metastasis to the liver. Proton beam therapy (PBT) is the preferred external radiotherapy treatment for primary UM of certain sizes and locations in the eye, due to its efficacy and good local tumour control, as well as its precision to spare surrounding ocular structures. PBT is an effective alternative to surgical enucleation and other non-precision-targeted radiotherapies. Despite this, the radiobiology of UM in response to PBT is still not fully understood. This enhanced knowledge would help to further optimise UM treatment and improve patient outcomes through reducing radiation dosage to ocular structures, treating larger tumours that would otherwise require enucleation, or even offering a treatment strategy for the otherwise fatal liver metastases. In this review, we explore current knowledge of the treatment of UM with PBT, evaluating the biological responses to the therapy. Molecular factors, such as tumour size, oxygen tension levels, DNA damage proficiency, and autophagy, are known to influence the cellular response to radiotherapy, and these will be discussed. Furthermore, we examine innovative strategies to enhance radiotherapy outcomes, such as combination therapies with DNA damage repair and autophagy modulators, as well as advancements in PBT planning and delivery. By integrating current research and emerging technologies, we aim to provide opportunities to improve the therapeutic effectiveness of PBT in UM management. Full article

Recent advances in biotechnology have fundamentally reshaped the landscape of vaccine development, offering innovative strategies to improve immunogenicity, safety and accessibility. This review explores the cutting-edge platforms—including mRNA, DNA, virus-like particles, viral and bacterial vectors, and bacteriophage-based vaccines—that are redefining how vaccine antigens are delivered to the immune system. We also discuss alternative delivery methods, such as transcutaneous and mucosal immunization, which have the potential to improve vaccine acceptance and distribution, as well as next-generation adjuvants targeting innate immune receptors aiming to further enhance vaccine efficacy, especially in vulnerable populations. By synthesizing these innovations, this review highlights how biotechnology is enabling the design of safer, more efficient, and more adaptable vaccines to address both existing and emerging infectious diseases. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a 5-year overall survival below 12% and high recurrence rates even after R0 resection. Traditionally managed with a “surgery-first” approach, two consistent observations—the near-universal presence of micrometastatic disease at diagnosis and the frequent inability to complete adjuvant therapy—have driven the integration of neoadjuvant therapy (NAT) into clinical practice. NAT offers several theoretical and practical advantages: early systemic control of occult disease, improved delivery and completion of multimodal treatment, biological selection of surgical candidates, and increased R0 resection rates. While in borderline resectable PDAC, randomized trials have consistently demonstrated improved margin-negative resection rates and early survival benefits compared with upfront surgery, in resectable PDAC, evidence is more heterogeneous. Real-world studies corroborate trial findings, reporting higher R0 rates and reduced lymph node positivity without increased perioperative risk, but also highlight substantial heterogeneity in regimens, duration, and radiotherapy use. Limitations to universal NAT adoption include reliance on anatomy-based resectability criteria, absence of validated predictive biomarkers, challenges in response assessment, and concerns over disease progression during preoperative treatment. Future developments will focus on integrating molecular profiling, circulating tumor DNA dynamics, and advanced imaging into patient selection and treatment adaptation, supported by biomarker-enriched and adaptive trial designs. NAT is thus evolving from a selective strategy for borderline disease to an innovative framework to optimize multimodal treatment delivery and refine patient selection in PDAC, with the potential to improve surgical outcomes and inform systemic therapy decisions in both resectable and borderline resectable settings Full article