Bacterial infection and severe inflammatory responses are major barriers to successful wound healing. Drug delivery systems have shown promise in precision medicine by enhancing the targeting and protection of therapeutic agents. However, their use is limited by challenges such as biocompatibility issues, structurally complex, high manufacturing costs, suboptimal drug loading, unstable release, and premature immune clearance. Although targeted delivery aims to improve efficacy, it may increase the risk of toxicity. Consequently, conventional non-carrier drugs often remain more practical and effective. Emerging vehicle-free systems with multifunctional capabilities show promise for precise targeting, controlled release, reduced toxicity, and simplified manufacturing. Here, we rationally designed and established a vehicle-free perfluoroalkyl material (PFAS)-gallium composites (PFASs@Ga) through introducing gallium (Ga) in PFASs, taking advantage of the collective merits of Ga's antibacterial and pro-healing properties and PFAS's well-recognized oxygen absorption, carrying of oxygen, chemical inertness, and tunable physicochemical properties. Extensive characterization showed well-defined morphology, elemental configuration, and distinct profiles of gallium ion release. The PFUnA@Ga composite improves gallium integration, Ga release, and O2 delivery. This allowed it to demonstrate potent broad-spectrum antibacterial activity against bacteria, including MRSA and E. coli, which are known to be resistant. In a MRSA-infected wound model, PFUnA@Ga enhances wound closure and reduces bacterial load, thereby promoting regeneration and angiogenesis. The downregulation of pro-inflammatory M1 macrophages and the upregulation of anti-inflammatory M2 macrophages and CD31+ endothelial cells, representing immunomodulatory effects that facilitate inflammation resolution and vascularization. Results confirmed the composites' antibacterial activity and accelerated wound-healing efficacy. This multifunctional composite offers a novel approach for advanced wound management. More specifically, the synergistic approach combines metal-ion mediated bacterial inactivation with sustained oxygenation to support infection control and tissue repair.

The rising resistance of conventional antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) and wound biofilm formation are major problems in treating bacterial infections and achieving successful wound healing. Artificial nanozymes that do not require antibiotics can generate sufficient reactive oxygen species (ROS) as a promising treatment option for antibacterial and biofilm eradication. To address this problem, we synthesized a triazole-based covalent organic framework (COF) and a copper-encapsulated COF (Tp-Tz COF & Cu@Tp-Tz COF), which were constructed via a one-pot method. This Cu@Tp-Tz COF possesses a superior photothermal and oxidase-like (OXD) activities responsible for ROS generation under near-infrared (NIR) irradiation to eradicate Gram-positive and Gram-negative multidrug-resistant (MDR) bacteria. The copper-anchored COF enhances the production of ROS through photothermal and OXD activity, resulting in significant antibacterial activity with over 90 % efficiency. The Cu@Tp-Tz COF-based nanozymes were shown to effectively destroy both Gram-positive and Gram-negative MDR bacteria in vitro. Tp-Tz COF and Cu@Tp-Tz COF uniformly disperse in water, remain stable, and show low cytotoxicity and minimal hemolysis of erythrocytes. Incorporating Cu@Tp-Tz COF into F127 hydrogel further enhances biocompatibility and functions as a protective skin barrier, inhibiting bacterial invasion and enabling effective wound sterilization. In addition, the high therapeutic potential of Cu@COF/FH was validated through analysis of tissue sectioning and immunofluorescent staining. The results emphasize the potential multifunctionality of Cu@COF/FH for antibacterial wound care as a comprehensive solution to wounds infected with MRSA. The findings from this work emphasize the need to develop Cu-anchored COFs with enhanced antimicrobial properties to address the issue of antimicrobial resistance.

BackgroundEwing sarcoma (ES) is a rare and aggressive pediatric bone malignancy with poor prognosis, driven by therapy-resistant tumor microenvironments (TME). The TME plays a critical role in tumor progression through a complex and dynamic network of reciprocal interactions among immune cells (dysfunctional T cells, immunosuppressive macrophages), stromal components (cancer-associated fibroblasts), and tumor cells. These interactions collectively shape the immune landscape, promote immune evasion, and contribute to therapeutic resistance. Identifying reliable prognostic markers remains a critical challenge.MethodsHere we performed an integrated single-cell RNA sequencing, WGCNA, and bulk RNA-seq analyses to investigate tumor-immune interactions. Differentially expressed genes (DEGs) intersected with T cell markers identified a total of 174 T cell-associated genes. Functional enrichment analysis and molecular subtyping were performed to explore immune-related pathways. A prognostic model based on CLEC11A, BDP1, and ID3 was constructed using Cox regression and validated in external datasets. Immune infiltration was assessed using the CIBERSORT algorithm.ResultsT cell marker analyses revealed key roles in pathways such as PI3K-Akt signaling and immune modulation. Molecular subtyping identified two clusters with distinct immune microenvironments: Cluster C1 (immunosuppressive phenotype and poorer prognosis) and Cluster C2 (functionally active immune profile associated with better prognosis). The prognostic model demonstrated high predictive accuracy for 1-, 3-, and 5-year survival (AUC: 0.85, 0.82, 0.78). Additionally, a higher tumor mutation burden (TMB) with low survival rate has been observed in High-risk group. Immune infiltration analysis showed higher CD8+ T cell and dendritic cell activity and immune checkpoint expression in low-risk groups. Experimental validation demonstrated that ID3 silencing inhibited tumor cell proliferation and induced cell cycle arrest in ES cell lines.ConclusionTogether, our study identified CLEC11A, BDP1, and ID3 as key T cell associated prognostic markers and developed a validated model to predict survival outcomes in ES. Insights into T cell markers and tumor-immune dynamics offer promising advances in prognostic assessment and immunotherapy for ES. Furthermore, the role of ID3 in immune evasion and tumor proliferation underscores its potential as a therapeutic target, providing new avenues for immune checkpoint regulation and personalized treatment strategies.

BackgroundFerroptosis and Cuproptosis are newly defined forms of cell death. Despite distinct mechanisms, both involve metabolic processes in the TCA cycle and downstream pathways, crucial for anticancer immunity.MethodsWe evaluated Iron (Fe) and Copper-induced cell death in lower-grade gliomas (LGG) using The Cancer Genome Atlas (TCGA) data by developing a metal-based ferroptosis and cuproptosis genes score (MBFCGs) risk model. Lasso regression and survival analyses assessed MBFCGs’ significance. An MBFCGs-based nomogram was created and its predictive performance verified. Signaling pathways, immune checkpoints, chemokines, and therapeutic response indicators were quantified using R/oncoPredict and Tidepay. Immunohistochemistry (IHC) examined candidate gene expression.ResultsThe MBFCGs risk model, based on BACH1, CDCA3, and TIMP1, predicts LGG prognosis. High MBFCGs were associated with poor clinical outcomes. Functional enrichment analysis showed upregulation in neurotransmitter receptor regulation, KRAS signaling, and hedgehog signaling pathways in the high-risk group. High-risk LGG patients exhibited higher tumor mutation burden (TMB) and lower IDH1 mutation incidence. These patients also had increased stromal and immune scores, with elevated levels of T helper cells, B cells, macrophages, neutrophils, and NK cells. Immune checkpoint analysis indicated higher expression of CD274, PDCD1, and other inhibitory molecules, suggesting potential for targeted cancer immunotherapy.ConclusionThe MBFCGs risk model is a promising prognostic tool for LGG, offering insights into underlying mechanisms and new directions for immunotherapy strategies. Assessment of MBFCGs for individual LGG patients may provide clues for developing new immunotherapy strategies.

Ovarian cancer (OC) is the deadliest gynecological malignancy, with a 5-year survival rate of 47%, primarily due to late diagnosis and platinum resistance. Although patients with OC often exhibit an initial clinical response to platinum-based chemotherapy, they typically develop resistance to platinum, posing a significant clinical challenge. Therefore, identifying effective biomarkers and potential therapeutic targets is critical. The PEST amino acid sequence, which comprises proline (P), glutamic acid (E), serine (S) and threonine (T), functions as a structural recognition motif for the cellular degradation machinery and modulates post-translational modifications (PTMs) of nuclear proteins (NPs), regulating their activation, localization and stability. PEST sequence-enriched NPs (PEST-NPs) act as oncogenes or tumor suppressors and influence cancer metabolism, immunity and transcription, and are thus potential therapeutic targets. The present review highlighted the multifaceted roles of PEST-NPs in types of OC, focusing on how PTMs of PEST domains mediate the activation, localization and stability of PEST-NPs. PTMs regulate the stability, activation and intracellular localization of PEST-NPs, thereby driving OC initiation, progression and chemoresistance. The present review also highlighted related hallenges and opportunities, including future research to facilitate the translation of PEST-NP-based OC diagnostics and therapies from the laboratory to the clinic. Future research insights will further support the development of diagnostic and therapeutic approaches for OC based on NPs, facilitating their translation from laboratory settings to applications.

Management of infected diabetic wounds with large amounts of biofluid is challenging to treat due to localized edema-induced ischemia. Traditional hydrophilic dressings retain wound exudate, raise bacterial infection, and hinder wound healing. Herein, a multifunctional double-layer Janus fibrous hydrogel with a hydrophobic and superhydrophilic potential was designed to accelerate the healing of infected diabetic wounds. The outer hydrophobic layer is composed of a poly(vinylidene fluoride)/cellulose acetate-based nanofibrous composite. In contrast, the inner superhydrophilic layer is composed of photo-cross-linked gelatin methacrylate/polycaprolactone based nanofibrous hydrogel coated with a zinc-dopamine-based metal-phenolic network complex. The bilayer Janus fibrous hydrogel was characterized for its structural, physicochemical, mechanical, swelling, antioxidant, antibacterial, and cytocompatibility properties. Results indicated that the outer hydrophobic layer possesses excellent antifouling self-cleaning potential and can prevent the entry of environmental microorganisms and moisture. On the other hand, the supramolecular complex coated inner layer possesses good antibacterial, antioxidant, and cell-supportive properties. Furthermore, the potential of Janus fibrous hydrogel for infected wound healing was evaluated by using infected diabetic BALB/c mice. The in vivo bacterial invasions and histological and immunological results indicated that the Janus fibrous hydrogel possesses good wound reconstruction potential, angiogenesis, and collagen deposition, making it appropriate for diabetic wound treatment.

Natural and synthetic hydrogels are beneficial for wound healing because of their biocompatibility, biodegradability, and capability to maintain a moist healing environment. Natural hydrogels, sourced from materials like hyaluronic acid (HA), chitosan, alginate, and collagen, replicate the extracellular matrix and play a vital role in cell migration, proliferation, and tissue regeneration. These materials promote wound healing by keeping a moist environment and offer inherent biological benefits, including anti-inflammatory, antioxidant, and antimicrobial properties. These contribute to accelerated healing and lower infection risk. For instance, chitosan is known for its antimicrobial properties, while HA can enhance tissue hydration and angiogenesis by developing new blood vessels. However, natural hydrogels face challenges like limited mechanical strength, instability, and variable degradation rates. These issues can hinder their long-term effectiveness in wound care applications. Natural hydrogels are often modified through crosslinking or combined with synthetic polymers to address these limitations. Combining both types into composite hydrogels offers a promising solution. Natural polymers enhance biological functions, while synthetic polymers improve mechanical strength. These hybrid hydrogels can also be loaded with bioactive agents like growth factors or stem cells to boost further healing. This combination addresses the limitations of each type, making composite hydrogels an ideal choice for wound dressings, specifically for chronic wounds and burns. Through merging the biological benefits of natural hydrogels with the customizable properties of synthetic ones, composite materials offer greater tissue regeneration, lowered healing time, and better clinical effects in wound care.

Diabetes significantly impairs the body’s wound-healing capabilities, leading to chronic, infection-prone wounds. These wounds are characterized by hyperglycemia, inflammation, hypoxia, variable pH levels, increased matrix metalloproteinase activity, oxidative stress, and bacterial colonization. These complex conditions complicate effective wound management, prompting the development of advanced diabetic wound care strategies that exploit specific wound characteristics such as acidic pH, high glucose levels, and oxidative stress to trigger controlled drug release, thereby enhancing the therapeutic effects of the dressings. Among the solutions, hydrogels emerge as promising due to their stimuli-responsive nature, making them highly effective for managing these wounds. The latest advancements in mono/multi-stimuli-responsive smart hydrogels showcase their superiority and potential as healthcare materials, as highlighted by relevant case studies. However, traditional wound dressings fall short of meeting the nuanced needs of these wounds, such as adjustable adhesion, easy removal, real-time wound status monitoring, and dynamic drug release adjustment according to the wound’s specific conditions. Responsive hydrogels represent a significant leap forward as advanced dressings proficient in sensing and responding to the wound environment, offering a more targeted approach to diabetic wound treatment. This review highlights recent advancements in smart hydrogels for wound dressing, monitoring, and drug delivery, emphasizing their role in improving diabetic wound healing. It addresses ongoing challenges and future directions, aiming to guide their clinical adoption.

Thymidylate kinase (TMPK) of monkeypox virus (MPXV) has emerged as a promising target for potential therapeutics due to its significant role in pyrimidine metabolism. While smallpox drugs are advised for treating monkeypox, the European Medicine Agency has sanctioned Tecovirimat due to its potent nanomolar activity. Nonetheless, there is a need for monkeypox-specific therapeutic options. In this work, we employed docking-based virtual screening and molecular dynamics (MD) simulations to identify myxobacterial secondary metabolites as promising anti-viral natural compounds capable of inhibiting thymidylate kinase. The computational pharmacokinetics and manual curation of top-scoring compounds identified six lead compounds that were compared in terms of protein-ligand contacts and protein-essential dynamics. The study shows that among the six candidates, Aurachin A and the Soraphinol analogues such as Soraphinol A and Soraphinol C remain very stable compared to other compounds, enabling the active site integrity via a stable dynamics pattern. We also show that other compounds such as Phenoxan, Phenylnannolone C, and 8E-Aurafuron B remain unstable and have a negative impact on the active site integrity and may not be suitable binders for TMPK protein. Analyzing the Aurachin A and Soraphinol A binding, the established hydrogen bonds with Arg93 and the conserved hydrophobic interaction with Tyr101 are consistent with previous experimental interactions. Additionally, a deeper insight into the indole and the aromatic ring interaction through π–π stacking and π-cation interactions, as well as the background of Aurachin A and Soraphinol A as a bioactive compound, has significant implications not only for its potential as a promising drug but also for directing future drug discovery efforts targeting the TMPK protein.

Lysosomal enzymes degrade cellular macromolecules, while their inactivation causes human hereditary metabolic disorders. Mucopolysaccharidosis IVA (MPS IVA; Moquio A syndrome) is one of the lysosomal storage disorders caused by a defective Galactosamine-6-sulfatase (GalN6S) enzyme. In several populations, disease incidence is elevated due to missense mutations brought on by non-synonymous allelic variation in the GalN6S enzyme. Here, we studied the effect of non-synonymous single nucleotide polymorphism (nsSNPs) on the structural dynamics of the GalN6S enzyme and its binding with N-acetylgalactosamine (GalNAc) using all-atom molecular dynamics simulation and an essential dynamics approach. Consequently, in this study, we have identified three functionally disruptive mutations in domain-I and domain-II, that is, S80L, R90W, and S162F, which presumably contribute to post-translational modifications. The study delineated that both domains work cooperatively, and alteration in domain II (S80L, R90W) leads to conformational changes in the catalytic site in domain-I, while mutation S162F mainly provokes higher residual flexibility of domain II. These results show that these mutations impair the hydrophobic core, implying that Morquio A syndrome is caused by misfolding of the GalN6S enzyme. The results also show the instability of the GalN6S-GalNAc complex upon substitution. Overall, the structural dynamics resulting from point mutations give the molecular rationale for Moquio A syndrome and, more importantly, the Mucopolysaccharidoses (MPS) family of diseases, re-establishing MPS IVA as a protein-folding disease.Communicated by Ramaswamy H. Sarma.

IntroductionZinc oxide nanoparticles (ZnO-NPs) have garnered considerable interest in biomedical research primarily owing to their prospective therapeutic implications in combatting pathogenic diseases and microbial infections. The primary objective of this study was to examine the biosynthesis of zinc oxide nanowhiskers (ZnO-NWs) using chicken egg white (albumin) as a bio-template. Furthermore, this study aimed to explore the potential biomedical applications of ZnO NWs in the context of infectious diseases.MethodsThe NWs synthesized through biological processes were observed using electron microscopy, which allowed for detailed examination of their characteristics. The results of these investigations indicated that the NWs exhibited a size distribution ranging from approximately 10 to 100 nm. Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) mapping analyses successfully corroborated the size, dimensions, and presence of biological constituents during their formation. In this study, XTT assay and confocal imaging were employed to provide evidence of the efficacy of ZnO-NWs in the eradication of bacterial biofilms. The target bacterial strains were Staphylococcus aureus and Escherichia coli. Furthermore, we sought to address pertinent concerns regarding the biocompatibility of the ZnO-NWs. This was achieved through comprehensive evaluation of the absence of cytotoxicity in normal HEK-293T and erythrocytes.ResultsThe findings of this investigation unequivocally confirmed the biocompatibility of the ZnO-NWs. The biosynthesized ZnO-NWs demonstrated a noteworthy capacity to mitigate the dermatitis-induced consequences induced by Staphylococcus aureus in murine models after a therapeutic intervention lasting for one week.DiscussionThis study presents a comprehensive examination of the biosynthesis of zinc oxide nanowhiskers (ZnO-NWs) derived from chicken egg whites. These findings highlight the considerable potential of biosynthesized ZnO-NWs as a viable option for the development of therapeutic agents targeting infectious diseases. The antibacterial efficacy of ZnO-NWs against both susceptible and antibiotic-resistant bacterial strains, as well as their ability to eradicate biofilms, suggests their promising role in combating infectious diseases. Furthermore, the confirmed biocompatibility of ZnO-NWs opens avenues for their safe use in biomedical applications. Overall, this research underscores the therapeutic promise of ZnO-NWs and their potential significance in future biomedical advancements.

BackgroundNuclear pore complexes (NPCs) are the architectures entrenched in nuclear envelop of a cell that regulate the nucleo-cytoplasmic transportation of materials such as proteins and RNAs for proper functioning of a cell. The appropriate localization of proteins and RNAs within the cell is essential for its normal functionality. For such a complex transportation of materials across the NPC, around 60 proteins are involved comprising nucleoporins, karyopherins and RAN system proteins that play a vital role in NPC’s structure formation, cargo translocation across NPC, and cargoes’ rapid directed transportation respectively. In various cancers, the structure and function of NPC is often exaggerated, following altered expressions of its nucleoporins and karyopherins, affecting other proteins of associated signaling pathways. Some inhibitors of karyopherins at present have potential to regulate the altered level/expression of these karyopherin molecules.Aim of ReviewThis review summarizes the data from 1990 to 2023, mainly focusing on recent studies that illustrate the structure and function of NPC, the relationship and mechanisms of nucleoporins and karyopherins with colorectal cancer, as well as therapeutic values, in order to understand the pathology and underlying basis of colorectal cancer associated with NPC. This is the first review to our knowledge elucidating the detailed updated studies targeting colorectal cancer at NPC. The review also aims to target certain karyopherins, nups and their possible inhibitors and activators molecules as a therapeutic strategy.Key Scientific Concepts of ReviewNPC structure provides understanding, how nucleoporins and karyopherins as key molecules are responsible for appropriate nucleocytoplasmic transportation. Many studies provide evidences describing the role of disrupted nucleoporins and karyopherins not only in CRC but also in other non-hematological and hematological malignancies. At present, some inhibitors of karyopherins have therapeutic potential for CRC, however development of more potent inhibitors may provide more effective therapeutic strategies for CRC in near future.

Self-healing hydrogels' remarkable dependability and enduring stability have made them stand out as extremely promising soft materials for tissue engineering. The mechanism behind their self-healing capabilities relies on reversible physical or chemical interactions that result in cross-linking. Researchers are designing and developing self-healing hydrogels with captivating characteristics such as impressive biocompatibility, responsiveness, conductivity, and mechanical and antibacterial properties. These desirable characteristics are tailored to meet the specific requirements of practical applications. This comprehensive review focuses on the latest progress in making hydrogels with self-healing properties and employing them to help heal wounds. Synthesis strategies may occasionally employ a combination of reversible physical or chemical cross-linking processes. Furthermore, the diverse therapies of these hydrogels encompass adhesive properties, wound-healing capabilities, drug-delivery systems, and more. Lastly, this review addresses self-healing hydrogels and tackles and explores future development prospects. The potential for these materials to revolutionize the area of tissue engineering is discussed, emphasizing their capability to overcome obstacles and pave the way for enhanced medical treatments.

>Intestinal wound healing is complex because of the intestine's intricate structure and the environment, which contains its microbes and digestive modules. Traditional suturing is the utmost standard surgical methodology, which can imply hyperplasia and obstruction, two probable harmful consequences. Thus, patients often face a delayed healing time and constrained healing experiences.

A controlled drug delivery system is highly desired in modern therapeutics. In this regard, nanotechnology plays a crucial role in covering adverse effects associated with chemotherapeutic agents, in terms of higher targeting ability, prolonged circulation half-life, and it exhibits higher biocompatibility features. Bionanocomposites are nanoscale materials composed of biopolymers that enhance nanomedicine efficacy by entrapping higher concentrations of drugs and excellent targeting ability. This chapter highlights various procedures and types of bionanocomposites employed in the drug delivery system and their applications in the biomedical realm.

Central nervous system disorders, especially neurodegenerative diseases, are a public health priority and demand a strong scientific response. Various therapy procedures have been used in the past, but their therapeutic value has been insufficient. The blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier is two of the barriers that protect the central nervous system (CNS), but are the main barriers to medicine delivery into the CNS for treating CNS disorders, such as brain tumors, Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. Nanotechnology-based medicinal approaches deliver valuable cargos targeting molecular and cellular processes with greater safety, efficacy, and specificity than traditional approaches. CNS diseases include a wide range of brain ailments connected to short- and long-term disability. They affect millions of people worldwide and are anticipated to become more common in the coming years. Nanotechnology-based brain therapy could solve the BBB problem. This review analyzes nanomedicine’s role in medication delivery; immunotherapy, chemotherapy, and gene therapy are combined with nanomedicines to treat CNS disorders. We also evaluated nanotechnology-based approaches for CNS disease amelioration, with the intention of stimulating the immune system by delivering medications across the BBB.

Drug delivery system (DDS) is of increased importance in terms of controlled and targeted release of a therapeutic entity that highly recognizes the target site. To date, several significant scaffolds as DDS have been introduced; among them, the hybridized realm has recently got more importance than single DDS because of addressing biocompatibility issues, higher blood circulation half-life, and target recognition. This chapter focuses on the major classes of hybridized nano-DDS, drug uploading modalities, controlled drug release types, and their applications in the biomedical realm.

Monkeypox (Mpox) is a virus that first emerged in Africa in 1970 [...].