Search Results (429)

Flavonoids constitute a broad class of naturally occurring chemical compounds classified as polyphenols, widely present in various plants, fruits, and vegetables. They share a common flavone backbone, composed of two aromatic rings (A and B) connected by a three-carbon bridge forming a heterocyclic ring (C). One representative flavonoid is chrysin, a compound found in honey, propolis, and passionflower (Passiflora spp.). Chrysin exhibits a range of biological activities, including antioxidant, anti-inflammatory, anticancer, neuroprotective, and anxiolytic effects. Its biological activity is primarily attributed to the presence of hydroxyl groups, which facilitate the neutralization of free radicals and the modulation of intracellular signaling pathways. Cellular uptake of chrysin and other flavonoids occurs mainly through passive diffusion; however, certain forms may be transported via specific membrane-associated carrier proteins. Despite its therapeutic potential, chrysin’s bioavailability is significantly limited due to poor aqueous solubility and rapid metabolism in the gastrointestinal tract and liver, which reduces its systemic efficacy. Ongoing research aims to enhance chrysin’s bioavailability through the development of delivery systems such as lipid-based carriers and nanoparticles. Full article

Recent studies have demonstrated the clinical potential of nucleic acid therapeutics (NATs). However, their efficient and scalable delivery remains a major challenge for both ex vivo and in vivo gene therapy. Microfluidic platforms have emerged as a powerful tool for overcoming these limitations by enabling precise intracellular delivery and consistent therapeutic carrier fabrication. This review examines microfluidic strategies for gene delivery at the cellular level. These strategies include mechanoporation, electroporation, and sonoporation. We also discuss the synthesis of lipid nanoparticles, polymeric particles, and extracellular vesicles for systemic administration. Unlike conventional approaches, which treat ex vivo and in vivo delivery as separate processes, this review focuses on integrated microfluidic systems that unify these functions. For example, genetic materials can be delivered to cells that secrete therapeutic extracellular vesicles (EVs), or engineered cells can be encapsulated within hydrogels for implantation. These strategies exemplify the convergence of gene delivery and carrier engineering. They create a single workflow that bridges cell-level manipulation and tissue-level targeting. By synthesizing recent technological advances, this review establishes integrated microfluidic platforms as being fundamental to the development of next-generation NAT systems that are scalable, programmable, and clinically translatable. Full article

Gene therapy is a groundbreaking strategy in regenerative medicine, enabling precise cellular behavior modulation for tissue repair. In situ nucleic acid delivery systems aim to directly deliver nucleic acids to target cells or tissues to realize localized genetic reprogramming and avoid issues like donor cell dependency and immune rejection. The key to success relies on biomaterial-engineered delivery platforms that ensure tissue-specific targeting and efficient intracellular transport. Viral vectors and non-viral carriers are strategically modified to enhance nucleic acid stability and cellular uptake, and integrate them into injectable or 3D-printed scaffolds. These scaffolds not only control nucleic acid release but also mimic native extracellular microenvironments to support stem cell recruitment and tissue regeneration. This review explores three key aspects: the mechanisms of gene editing in tissue repair; advancements in viral and non-viral vector engineering; and innovations in biomaterial scaffolds, including stimuli-responsive hydrogels and 3D-printed matrices. We evaluate scaffold fabrication methodologies, nucleic acid loading–release kinetics, and their biological impacts. Despite progress in spatiotemporal gene delivery control, challenges remain in balancing vector biocompatibility, manufacturing scalability, and long-term safety. Future research should focus on multifunctional “smart” scaffolds with CRISPR-based editing tools, multi-stimuli responsiveness, and patient-specific designs. This work systematically integrates the latest methodological advances, outlines actionable strategies for future investigations and advances clinical translation perspectives beyond the existing literature. Full article

Cell-penetrating peptides offer a promising strategy for intracellular delivery; however, non-specific uptake and off-target cytotoxicity limit their clinical utility. To address these limitations, a cold atmospheric plasma-responsive delivery platform was developed in which the membrane activity of a peptide was transiently suppressed upon complexation with a DNA-based nanostructure. Upon localized plasma exposure, DNA masking was disrupted, restoring the biological functions of the peptides. Transmission electron microscopy revealed that the synthesized DNA nanoflower structures were approximately 150–250 nm in size. Structural and functional analyses confirmed that the system remained inert under physiological conditions and was rapidly activated by plasma treatment. Fluorescence recovery, cellular uptake assays, and cytotoxicity measurements demonstrated that the peptide activity could be precisely controlled in both monolayer and three-dimensional spheroid models. This externally activatable nanomaterial-based system enables the spatial and temporal regulation of peptide function without requiring biochemical triggers or permanent chemical modifications. This platform provides a modular strategy for the development of potential peptide therapeutics that require precise control of activation in complex biological environments. Full article

Background/Objectives: Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains a major neglected tropical disease, with over six million cases concentrated, primarily in Latin America. Despite decades of research, treatment continues to rely on two outdated drugs—benznidazole and nifurtimox—both of which exhibit limited efficacy and are associated with severe side effects. In this context, drug repurposing presents a promising strategy to accelerate the development of safer and more effective therapies. Nitroxoline, a hydroxyquinoline compound widely used in Europe to treat bacterial urinary tract infections, has recently garnered attention for its broad-spectrum antimicrobial and anticancer activities. This study evaluated the antitrypanosomal potential of nitroxoline against both epimastigote and intracellular amastigote forms of T. cruzi, demonstrating significantly greater efficacy than benznidazole. Methods: In addition to its antiparasitic activity, we investigated the mechanism of parasite death and found that nitroxoline induces hallmarks of programmed cell death, including chromatin condensation, mitochondrial membrane depolarization, ATP depletion, reactive oxygen species accumulation, and increased membrane permeability. These cellular events are critical for minimizing host tissue inflammation and suggest a safer therapeutic profile. Results: The nitroxoline was shown to induce greater activity than the reference treatment, benznidazole, in addition to triggering events related to apoptotic or silent cell death. Conclusions: Given its established clinical use and favorable safety data, nitroxoline emerges as a strong candidate for further investigation as a repurposed treatment for Chagas disease. Future work should focus on in vivo efficacy, pharmacokinetics, and drug delivery strategies to enhance systemic bioavailability. Full article

CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9)-mediated genome editing has emerged as a transformative tool in medicine, offering significant potential for cancer therapy because of its capacity to precisely target and alter the genetic modifications associated with the disease. However, a major challenge for its clinical translation is the safe and efficient in vivo delivery of CRISPR/Cas9 components to target cells. Nanotechnology is a promising solution to this problem. Nanocarriers, owing to their tunable physicochemical properties, can encapsulate and protect CRISPR/Cas9 components, enabling targeted delivery and enhanced cellular uptake. This review provides a comprehensive examination of the synergistic potential of CRISPR/Cas9 and nanotechnology in cancer therapy and explores their integrated therapeutic applications in gene editing and immunotherapy. A critical aspect of in vivo CRISPR/Cas9 application is to achieve effective localization at the tumor site while minimizing off-target effects. Nanocarriers can be engineered to overcome biological barriers, thereby augmenting tumor-specific delivery and facilitating intracellular uptake. Furthermore, their design allows for controlled release of the therapeutic payload, ensuring sustained efficacy and reduced systemic toxicity. The optimization of nanocarrier attributes, including size, shape, surface charge, and composition, is crucial for improving the cellular internalization, endosomal escape, and nuclear localization of CRISPR/Cas9. Moreover, surface functionalization with targeting ligands can enhance the specificity of cancer cells, leading to improved gene-editing accuracy. This review thoroughly discusses the challenges associated with in vivo CRISPR/Cas9 delivery and the innovative nanotechnological strategies employed to overcome them, highlighting their combined potential for advancing cancer treatment for clinical application. Full article

Natural polymer-based nanoparticles have emerged as promising stabilizers for Pickering emulsions, offering biocompatibility, environmental sustainability, and improved protection of active compounds. This study developed chitosan/gum arabic (CH/GA) nanoparticles as solid stabilizers for quercetin-loaded Pickering emulsions to enhance the stability and antioxidant bioactivity of quercetin (QE), a plant-derived flavonoid known for its potent radical-scavenging activity but limited by oxidative degradation. A systematic formulation strategy was employed to evaluate the effects of CH/GA concentration (0.5–2.0% w/v), oil type (olive, soybean, sunflower, and coconut), and oil volume fraction (ϕ = 0.5–0.7) on emulsion stability. The formulation containing 1.5% CH/GA and olive oil at ϕ = 0.6 exhibited optimal physical and interfacial stability. Quercetin (0.1% w/w) was incorporated into the optimized emulsions and characterized for long-term stability, particle size, droplet morphology, rheology, antioxidant activity (DPPH), cytocompatibility, and intracellular reactive oxygen species (ROS) protection using HaCaT keratinocytes. The olive oil-based formulation (D1-QE) exhibited greater viscosity retention and antioxidant stability than its soybean-based counterpart (E2-QE) under both room temperature (RT) and accelerated heating–cooling (H/C) storage conditions. Confocal microscopy confirmed the accumulation of CH/GA nanoparticles at the oil–water interface, forming a dense interfacial barrier and enhancing emulsion stability. HPLC analysis showed that D1-QE retained 92.8 ± 0.5% of QE at RT and 82.8 ± 1.5% under H/C conditions after 30 days. Antioxidant activity was largely preserved, with only 4.7 ± 1.7% and 14.9 ± 4.8% loss of DPPH radical scavenging activity at RT and H/C, respectively. Cytotoxicity testing in HaCaT keratinocytes confirmed that the emulsions were non-toxic at 1 mg/mL QE and effectively reduced H₂O₂-induced oxidative stress, decreasing intracellular ROS levels by 75.16%. These results highlight the potential of CH/GA-stabilized Pickering emulsions as a polymer-based delivery system for maintaining the stability and functional antioxidant activity of QE in bioactive formulations. Full article

Background: Metastatic prostate cancer (mPrC), with a median survival of under 2 years, represents an important unmet medical need which may benefit from the development of more effective targeted drug delivery systems. Several cell surface receptors have been identified as candidates for targeted drug delivery to mPrC cells; however, these receptors were selected for their overabundance on PrC cells rather than for their suitability for targeted delivery and uptake of cytotoxic drug payloads. Methods: We describe a novel, unbiased strategy to isolate peptides that fulfill functional criteria required for effective intracellular drug delivery and the specific cytotoxicity of PrC cells without prior knowledge of the targeted receptor. Phage clones displaying 7-mer cyclic peptides were negatively selected in vivo and then positively biopanned through a series of parent and drug-resistant mPrC cells. Peptides from the internalized clones were then subjected to a panel of biochemical and functional tests that led to the selection of several peptide candidates. Results: The selected peptides do not bind PSMA. Peptide-drug conjugates (PDCs) incorporating one of the peptides selectively killed wild-type and drug-resistant PrC cell lines and patient PrC cells but not normal prostate tissue cells in vitro. The PDC also halted the growth of PC3 tumors in a xenograft model. Conclusions: Our study demonstrates that adding unbiased, functional criteria into drug carrier selection protocols can lead to the discovery of novel peptides with appropriate properties required for effective targeted drug delivery into target cancer cells. Full article

mRNA-based drug development is revolutionizing tumor therapies by enabling precise cancer immunotherapy, tumor suppressor gene restoration, and genome editing. However, the success of mRNA therapies hinges on efficient delivery systems that can protect mRNA from degradation and facilitate its release into the cytoplasm for translation. Despite the emergence of lipid nanoparticles (LNPs) as a clinically advanced platform for mRNA delivery, the efficiency of endo/lysosomal escape still represents a substantial bottleneck. Here, we summarize the intracellular fate of mRNA-loaded LNPs, focusing on their internalization pathways and processing within the endo-lysosomal system. We also discuss the impact of endo-lysosomal processes on mRNA delivery and explore potential strategies to improve mRNA escape from endo-lysosomal compartments. This review focuses on molecular engineering strategies to enhance LNP-mediated endo/lysosomal escape by optimizing lipid composition, including ionizable lipids, helper lipids, cholesterol, and PEGylated lipids. Additionally, ancillary enhancement strategies such as surface coating and shape management are discussed. By comprehensively integrating mechanistic insights into the journey of LNPs within the endo-lysosome system and recent advances in lipid chemistry, this review offers valuable inspiration for advancing mRNA-based cancer therapies by enabling robust protein expression. Full article

Cuproptosis, a newly discovered copper-dependent programmed cell death pathway, represents a promising approach for anticancer therapy. However, the efficacy of cuproptosis critically depends on intracellular copper accumulation. Traditional copper ionophores have limited therapeutic efficacy due to their reliance on serum copper levels. Therefore, the development of novel copper ionophores to enhance intracellular copper levels is urgently needed. In this study, we targeted a melanoma model and pioneered the application of Bis(2-hydroxyethyl)dithiocarbamic acid copper(II) [Cu(HEDTC)₂] as a highly efficient copper ionophore for inducing cuproptosis in B16 melanoma cells. Compared to conventional copper ionophores, Cu(HEDTC)₂ exhibits superior intracellular copper delivery efficiency, thereby enhancing the induction of cuproptosis. We further constructed a Cu(HEDTC)₂@Soluplus-nanomicelle (CS NM) system designed to disrupt copper ion homeostasis in tumor cells and amplify cuproptosis. In this system, Cu(HEDTC)₂, as a novel copper ionophore, significantly enhanced the copper level in B16 melanoma cells. Upon cellular internalization, CS NM underwent degradation and released copper ions, which subsequently triggered cuproptosis by causing abnormal aggregation of mitochondrial lipoylated proteins. This study provides a new experimental foundation and potential therapeutic strategy for cuproptosis-based cancer treatment. Full article

Background: Intracellular bacteria frequently result in chronic and recurrent infections. MRSA is one of the most prevalent facultative intracellular bacteria in clinical infections. The drug resistance of MRSA and the difficulty of most antibiotics in entering cells result in a suboptimal clinical efficacy of antibiotics in the treatment of intracellular MRSA. Bacteriophages represent a promising alternative therapy in the context of the current antimicrobial resistance crisis. Nevertheless, the low efficiency of phage entry into cells and their rapid inactivation remain challenges in the treatment of intracellular MRSA using phages. The utilization of functionalized carriers for the delivery of phages into cells and their protection represents a feasible strategy. Methods: In this study, a new MRSA bacteriophage (vB_SauS_PHM) was isolated from hospital sewage, exhibiting the characteristics of short incubation period, large lytic amount, and good environmental tolerance. Subsequently, vB_SauS_PHM was encapsulated by TAT peptide-functionalized liposomes through microfluidic technology and size-exclusion chromatography (SEC), forming a phage delivery system, designated TAT-Lip@PHM. Results: The encapsulation rate of the phage by TAT-Lip@PHM was 20.3%, and the cell entry efficiency was ≥90% after 8 h. The 24 h eradication rate of 300 μg/mL TAT-Lip@PHM against intracellular MRSA was 94.05% (superior to the 21.24% and 44.90% of vB_SauS_PHM and Lip@PHM, respectively), while the mammalian cell activity was >85% after 24 h incubation. Conclusions: The TAT-Lip@PHM effectively delivered the phage into the cell and showed an excellent killing effect on intracellular MRSA with low cytotoxicity. This work provides a technical reference for the application of phages in the treatment of intracellular bacterial infection. Full article

Antioxidants neutralize reactive oxygen species and free radicals, protecting cells from oxidative damage and maintaining cellular homeostasis. In cancer therapy, they play a complex dual role, serving as protective agents against oxidative stress while, under certain conditions, acting as pro-oxidants that may promote tumorigenesis and resistance to treatment. Redox regulation is governed by key antioxidant pathways, such as the BACH1 and NRF2 pathways, along with transcriptional factors that significantly affect cancer progression and immunotherapy response. In addition to their intracellular effects, antioxidants modulate the tumor microenvironment, including interactions with the extracellular matrix, which impact cancer cell behavior and therapeutic responses. This review also explores preclinical studies that investigate the roles of major antioxidants in cancer biology. While these studies present promising data, significant challenges persist, including the potential for antioxidants to interfere with standard cancer treatments or to inadvertently support tumor survival. We further highlight emerging strategies aimed at optimizing antioxidant therapy, including personalized medicine approaches, nanoparticle-based delivery systems, and combination treatments with immunotherapies and targeted therapies. By examining the therapeutic potential and associated risks of antioxidants, this review provides critical insights into their role in cancer treatment and offers a roadmap for advancing antioxidant-based strategies to improve clinical outcomes. Full article

Severe systemic toxicity and poor targeting efficiency remain major limitations of traditional chemotherapy, emphasising the need for smarter drug delivery systems. Magnetic 2D transition-metal-based nanomaterials offer a promising approach, as they can be designed to combine high drug loading, precise targeting, and controlled release. The key material classes—transition metal dichalcogenides, transition metal carbides/nitrides, transition metal oxides, and metal–organic frameworks—share important physicochemical properties. These include high surface-to-volume ratios, tuneable functionalities, and efficient intracellular uptake. Incorporating magnetic nanoparticles into these 2D structures broadens their potential beyond drug delivery, through enabling multimodal therapeutic strategies such as hyperthermia induction, real-time imaging, and photothermal or photodynamic therapy. This review outlines the potential of magnetic 2D transition-metal-based nanomaterials for biomedical applications by evaluating their therapeutic performance and biological response. In parallel, it offers a critical analysis of how differences in physicochemical properties influence their potential for specific cancer treatment applications, highlighting the most promising uses of each in bionanomedicine. Full article

Drug delivery systems have revolutionized the clinical field by enabling the targeted, controlled, and sustained release of therapeutic agents, minimizing side effects and maximizing efficacy. Among the various drug delivery platforms, polymer-based systems have gained significant attention due to their versatility and biocompatibility. This study investigates the release of dexamethasone and clobetasol propionate from PLA (poly(lactic acid)) fibers in a cellular culture system. The release profiles were analyzed over 1, 6, and 24 h using high-performance liquid chromatography (HPLC), showing a gradual, continuous release, with clobetasol exhibiting slower release due to its poor water solubility. The presence of fibroblasts did not significantly affect the drug release, and the concentrations increased over time. An intracellular recovery test revealed that both drugs entered the cells, although their concentrations were below the limit of quantification (LOQ). Measurements of the remaining drug in the fibers confirmed a sustained release, with no significant difference between conditions with and without cells. These results highlight the potential of PLA fibrous membranes for controlled drug delivery, though further research is needed to optimize release and improve intracellular quantification for more effective therapeutic applications. Full article

The spleen, the largest secondary lymphoid organ, plays several vital roles in the body, including blood filtration, hematopoiesis, and immune regulation. Despite its importance, the spleen has not received substantial attention as a target organ for drug delivery. Most systemically administered colloidal and particulate drug carriers are cleared from the blood by the liver and spleen, making these two organs potential targets for drug accumulation. While various systems have been developed to target the liver, there is an urgent need to design spleen-targeted drug delivery systems that can evade clearance and degradation while delivering drugs efficiently to their target cells in the spleen. Targeting the spleen holds great potential for the treatment of a range of diseases, including blood disorders, immune and inflammatory diseases, infectious diseases, and cancer. It is also crucial for the development of effective vaccines. In this review, we explore different approaches used to target the spleen after systemic administration, and we discuss the factors that shift the biodistribution of drug carriers from the liver to the spleen. We focus on cell-specific delivery within the spleen, strategies to avoid degradation, and methods to achieve the efficient intracellular delivery of various drugs and genes. We also highlight the therapeutic implications of spleen-targeted drug delivery systems, particularly for the prevention and treatment of cancer. Full article