International Journal of Nanomedicine

Purpose Trichinella spiralis has evolved complex immunomodulatory mechanisms mediated by excretory-secretory products (ESL1) that enable its survival in the host. Consequently, ESL1 antigens display excellent potential for treating autoimmune diseases such as multiple sclerosis (MS). However, whether timely controlled delivery of ESL1 antigens in vivo, as in natural infections, could enhance its therapeutic potential for MS is still unknown. Methods To test this, we encapsulated ESL1 antigens into biodegradable poly (lactide-co-glycolic) acid (PLGA) nanofibers by emulsion electrospinning as a delivery system and assessed their release dynamics in vitro, and in an animal MS model, experimental autoimmune encephalomyelitis (EAE), induced 7 days after PLGA/ESL1 subcutaneous implantation. PLGA/ESL1 effects on EAE symptoms were monitored along with multiple immune cell subsets in target organs at the peak and recovery of EAE. Gut barrier function and microbiota composition were analyzed using qPCR, 16S rRNA sequencing, and metabolomic analyses. Results ESL1 antigens, released from PLGA and drained via myeloid antigen-presenting cells through lymph nodes, protected the animals from developing EAE symptoms. These effects correlated with reduced activation of myeloid cells, increased IL-10 expression, and reduced accumulation of proinflammatory natural killer (NK) cells, T helper (Th)1 and Th17 cells in the spleen and central nervous system (CNS). Additionally, CD4⁺CD25hiFoxP3⁺ regulatory T cells and IL-10-producing B cells were expanded in PLGA/ESL1-treated animals, compared to control animals. The migration of ESL1 to the guts correlated with locally reduced inflammation and gut barrier damage. Additionally, PLGA/ESL1-treated animals displayed an unaltered microbiota characterized only by a more pronounced protective mevalonate pathway and expanded short-chain fatty acid-producing bacteria, which are known to suppress inflammation. Conclusion The delivery of T. spiralis ESL1 antigens via biodegradable electrospun PLGA nanofiber implants efficiently protected the animals from developing EAE by inducing a beneficial immune response in the spleen, gut, and CNS. This platform provides excellent grounds for further development of novel MS therapies.

Background 5-fluorouracil (5-FU) is the most widely used anti-pyrimidine drug that exerts its cytotoxic effect by causing DNA damage. The Wnt/β-catenin pathway has been considered a promising strategy to improve chemosensitivity by enhancing the DNA damage response of chemotherapy drugs. Combination therapies against cancers could inevitably affect endogenous levels of ribonucleotides (RNs) and deoxyribonucleotides (dRNs) which are critical for DNA synthesis and repair. However, exploring satisfactory Wnt/β-catenin inhibitors for synergistic therapy through regulating RNs and dRNs remains challenging. Methods and Results Here, aloe vera-derived carbon dots (A-CDs) with good bioactivity were synthesized via a one-step hydrothermal process, demonstrating both intrinsic Wnt/β-catenin inhibition and bioimaging capabilities to overcome the limitations of conventional Wnt/β-catenin inhibitors. The as-prepared A-CDs were further served as the transport vehicle for 5-FU, facilitating synergistic combination therapy by inhibiting the Wnt/β-catenin pathway, which could possibly accelerate nucleotide imbalance of dATP, ATP, TMP, and dUMP, ultimately leading to enhanced 5-FU efficiency. Additionally, the tumor-targeted material (HA-CDs@5-FU) was synthesized by modifying hyaluronic acid (HA) onto CDs@5-FU and exhibited superior antitumor efficacy in vivo with negligible side effects. Conclusion Overall, this study provided a novel strategy for Wnt/β-catenin inhibition and synergistic therapy, providing insights into the application of nano-agents in cancer therapy.

Purpose Limb ischemia is a refractory disease characterized by insufficient angiogenesis and tissue necrosis. Currently, the primary clinical treatment method is surgical intervention; however, the prognosis for patients with severe limb ischemia remains unsatisfactory. Although some studies have evaluated the effects of using bioactive factors to promote neovascularization and tissue repair, the clinical outcomes have not met expectations, possibly due to the difficulties in maintaining biological activity and avoiding potential side effects. Traditional Chinese medicine, specifically astilbin (AST), is a potential therapeutic agent in promoting tissue regeneration. However, there have been no reports on its efficacy in treating limb ischemia through promoting angiogenesis. Materials and Methods In this study, we prepared AST-loaded lignin nanoparticles (LNP/AST) with sustained-release functionality, which were mixed with GelMA hydrogel (GelMA@LNP/AST). The angiogenic effects were evaluated in a mouse model of hind limb ischemia. To further investigate the mechanism of angiogenesis, human endothelial cell line EA.hy926 was exposed to different concentrations of AST. The effects of AST on cell migration and angiogenesis were studied using wound healing assays and angiogenesis assays. The changes in angiogenesis markers, autophagy markers, and eNOS levels were detected using qPCR and Western blotting. 3-MA was used to assess the role of autophagy in the activation of eNOS mediated by AST and its subsequent angiogenic effects. Results GelMA@LNP/AST significantly promoted blood flow recovery in mice with hind limb ischemia. This effect was mainly attributed to the enhanced migration and angiogenic capabilities of endothelial cells mediated by AST. A potential underlying mechanism could be that the autophagy induced by AST increases eNOS activity. Conclusion GelMA@LNP/AST enables complete revascularization in female mice after hind limb ischemia, thereby achieving limb preservation and restoring motor function. Given the good therapeutic potential of the GelMA@LNP/AST in revascularization, it may become an effective strategy for successfully salvaging limbs in cases of limb ischemia.

Background The development of selective formulations able to target and kill tumor cells without the application of external energy has shown great promise for anti-tumor therapy. Methods Here, we report a “nanobomb” that explosively increases Ca content within cells. It can selectively release Ca²⁺ and generate H2O2 in the tumor microenvironment (TME) by acid-triggered degradation of the two-layer protective shell (ie, unlocking the “double-lock”). This material, termed CaO2@ZIF8:CUR@PAA, comprises a CaO2 core coated with the ZIF-8 framework, which was then loaded with curcumin (CUR) and coated again with polyacrylic acid (PAA). Results Under the slightly acidic conditions of the TME, the PAA shell (first lock) breaks down first exposing CaO2@ZIF8 and CUR inside the cell. Then, ZIF8 (second lock) is degraded in response to acid to deposit Ca²⁺, and H2O2. CUR can promote the release of Ca²⁺ from the endoplasmic reticulum to the cytoplasm, inhibit the outflow of Ca²⁺, and accumulates a large amount of Ca²⁺ intracellularly together with exogenous Ca²⁺ (calcium storms). The powerful calcium storm that causes mitochondrial dysfunction. The presence of a large amount of exogenous H2O2 causes further oxidative damage to tumor cell membranes and mitochondria where intracellular ROS production far exceeds clearance. CaO2@ZIF8:CUR@PAA NPs can induce cell S cycle arrest and apoptosis to inhibit tumor multiplication and growth. Oxidative damage-triggered immunogenic cell death (ICD) in turn leads to the polarization of macrophages to the M1 phenotype, inducing immunogenic cell death and inhibiting tumor cell proliferation and metastasis. Discussion The acid two-step unlocking nanoplatform is a therapeutic modality that combines calcium storm and oxidative damage. The mode triggers apoptosis leading to ICD of tumor cells. The material induces cycle blockade during treatment to inhibit cell proliferation. Robust in vitro and in vivo data demonstrate the efficacy of this approach and CaO2@ZIF8:CUR@PAA as an anticancer platform, paving the way for nanomaterials in immune-triggered cancer therapy.

Purpose Myocardial ischemia-reperfusion (IR) injury, a significant challenge in cardiovascular treatment, is primarily driven by ferroptosis and mitochondrial dysfunction. Despite extensive research, no clinical therapies effectively target ferroptosis in IR injury. This study aims to develop selenium-quantum-dot-loaded porous silica nanospheres (Se@PSN) as a novel therapeutic approach to address IR injury. Patients and Methods Se@PSN were synthesized and tested for their reactive oxygen species (ROS) scavenging capabilities and biocompatibility. Additionally, the effects of Se@PSN on ferroptosis, mitochondrial damage, oxidative stress, and myocardial IR injury severity were evaluated. Results Se@PSN enhanced the stability of selenium quantum dots and exhibited strong ROS scavenging abilities. Additionally, Se@PSN exhibited excellent biocompatibility. The Se@PSN treatment increased GPX4 levels, effectively inhibiting ferroptosis in cardiomyocytes. Furthermore, Se@PSN promoted the expression of mitochondrial respiratory complexes, mitigating oxidative phosphorylation damage and preserving mitochondrial function. These effects collectively resulted in reduced myocardial loss, inflammation, and fibrosis following IR injury. Compared to PSN alone, Se@PSN showed superior therapeutic efficacy against IR injury. Conclusion Se@PSN exhibit great potential in reducing ferroptosis and protecting mitochondrial function, making them a promising therapeutic approach for the treatment of myocardial IR injury.

Purpose Study aims to optimize the synthesis conditions for silver nanoparticle composites [ALP(D)-AgNPs] using a rapid and environmentally friendly method and investigate the antioxidant, antibacterial, and anticancer activities of the fabricated composite. Methods The polysaccharide component ALP-D was extracted and purified from the fruits of Amomum longiligulare and subsequently used for further experiments. The structure of ALP-D was characterized by FT-IR, monosaccharide composition and molecular weight.The optimal conditions for the green synthesis of silver nanoparticles using ALP-D were determined through single-factor experiments. The synthesized silver nanoparticles were characterized by UV-Vis spectroscopy, FT-IR, DLS, HRTEM and XRD. Finally, the in vitro antioxidant activity, antibacterial activity and anticancer activity of the nano-silver composite were evaluated. Results Single-factor experiments identified the optimal synthesis conditions for ALP(D)-AgNPs as a reaction time of 180 min, a temperature of 100 °C, and a 10:1 volume ratio of silver nitrate to ALP-D. The free radical scavenging activity of ALP(D)-AgNPs against DPPH and ABTS was significantly enhanced compared with that of ALP-D. The minimum inhibitory concentration (MIC) values of ALP(D)-AgNPs against E coli and B subtilis were 31.25 μg/mL, while the MIC value against S aureus was 62.5 μg/mL. The minimum bactericidal concentration (MBC) values of ALP(D)-AgNPs were 125 μg/mL for E coli, B subtilis, and S aureus. The IC50 values of ALP(D)-AgNPs on the MDA-MB-231, HepG2, Caco-2, and C6 cancer cell lines were 14.72 ± 0.23, 8.19 ± 0.65, 22.73 ± 3.01, and 15.77 ± 2.91 μg/mL, respectively. Conclusion In summary, we have identified a novel material for the green synthesis of silver nanoparticles. The results show the ALP(D)-AgNPs synthesized using the new material ALP-D exhibit excellent stability and dispersibility. Furthermore, the biological activity reveals that ALP(D)-AgNPs possess notable antioxidant, antibacterial, and cancer-suppressing activities.

Purpose Human noroviruses (HuNoVs) are the main cause of non-bacterial acute gastroenteritis. Due to antigenic diversity, the discovery of ligands that can sensitively and specifically detect HuNoVs remains challenging. Limited by laboratory culture, no vaccines or drugs have been developed against HuNoVs. Here, we screened nucleic acid aptamers against the widespread HuNoV GII.4 and emerging HuNoV GII.17. Methods After ten rounds of sieving for HuNoV GII.4 and GII.17 virus-like particles (VLPs), eight ssDNA aptamers were generated and characterized for each genotype. Results Four of the eight aptamers generated for GII.4 VLP had dissociation constants (Kd) less than 100 nM, and all aptamers for GII.17 VLP had Kd less than 10 nM. All aptamers bound to their targets in VLP concentration-dependent manner. Two aptamers (AP4-2 and AP17-4) were selected for enzyme-linked aptamer sorbent assay (ELASA) and further analysis. Binding affinity was enhanced as the concentration of both aptamer and VLPs increased. The specificity of the aptamers was verified by ELASA and dot blotting. AP4-2 and AP17-4 were able to differentiate HuNoV from other diarrhea-causing pathogens or unrelated proteins (P < 0.0001). VLP/porcine gastric mucin (PGM) binding blockade assays revealed that AP4-2 and AP17-4 blocked the binding of HuNoV VLPs to PGM. VLP internalization inhibition assays showed that at a concentration of 0.5 µM, both AP4-2 and AP17-4 effectively inhibited attachment and internalization of HuNoV VLPs into 293T cell (P < 0.05). Cell viability assays confirmed that aptamers did not induce cellular toxicity. Conclusion AP4-2 and AP17-4 showed strong affinity and specificity for their target VLPs and represent promising candidates for HuNoV capture and detection. This is the first study to demonstrate that aptamers can effectively inhibit HuNoV VLPs from binding to or entering cells, thus providing a new concept for the treatment of HuNoVs.

Myocardial infarction (MI) is the leading cause of mortality from cardiovascular diseases. Rapid diagnosis and effective treatment are critical for improving patient prognosis. Although current diagnostic and therapeutic approaches have made significant progress, they still face challenges such as ischemia-reperfusion injury, microcirculatory disorders, adverse cardiac remodeling, and inflammatory responses. These issues highlight the urgent need for innovative solutions. Nanomaterials, with their diverse types, excellent physicochemical properties, biocompatibility, and targeting capabilities, offer promising potential in addressing these challenges. Advances in nanotechnology have increasingly drawn attention to the application of nanomaterials in both diagnosing and treating myocardial infarction. We summarize the pathophysiological mechanisms and staging of myocardial infarction. We systematically review the applications of nanomaterials in MI diagnosis, including the detection of biomarkers and imaging techniques, as well as in MI treatment, encompassing anti-inflammatory effects, antioxidant stress, inhibition of fibrosis, promotion of angiogenesis, and cardiac conduction repair. We analyze the existing challenges and provide insights into future research directions and potential solutions. Specifically, we discuss the need for rigorous safety assessments, long-term efficacy studies, and the development of robust strategies for translating laboratory findings into clinical practice. In conclusion, nanotechnology holds significant promise as a new strategy for diagnosing and treating myocardial infarction. Its potential to enhance clinical outcomes and revolutionize patient care makes it an exciting area of research with practical applications in real-world clinical settings.

Spinal cord injury (SCI) is a very destructive disease of the central nervous system that often causes irreversible nerve damage. Unfortunately, the adult mammalian spinal cord displays little regenerative capacity after injury. In addition, the glial scars and inflammatory responses around the lesion site are another major obstacle for successful axon regeneration after SCI. However, biomaterials are highly biocompatible, and they could provide physical guidance to allow regenerating axon growth over the lesion site and restore functional neural circuits. In addition, combined or synergistic effects of spinal cord repair can be achieved by integrating different strategies, including the use of various biomaterials and microstructures, as well as combining bioactive molecules and living cells. Therefore, it is possible to use tissue engineering scaffolds to regulate the local microenvironment of the injured spinal cord, which may achieve better functional recovery in spinal cord injury repair. In this review, we summarize the latest progress in the treatment of SCI by biomaterials, and discussed its potential mechanism.

Introduction Photothermal therapy (PTT) is attracting increasing attention in treating atherosclerotic plaques. However, PTT can induce inflammatory responses, in turn stimulating the regeneration of atherosclerosis and hindering subsequent therapy. Methods In this paper, a multifunctional nanoparticle (Au NR@SiO2/RSNO/DS, GSNPD) for the synergistic treatment of atherosclerosis through PTT and anti-inflammation effects was developed. The preparation and characterization of GSNPD, their cellular toxicity, photothermal conversion and targeted ablation efficiency, anti-inflammation and ROS scavenging effect, as well as the inhibition of foam cell formation were studied in vitro. Results The experimental results showed that the fabricated GSNPD NPs displayed positive effects on anti-atherosclerosis by pro-inflammatory macrophages ablation, NO production and ROS scavenging. Discussion GSNPD NPs were designed to effectively and accurately ablate pro-inflammatory macrophages by recognizing and targeting to SR-A overexpressed on the activated macrophages of arterial plaques via PTT, and simultaneous inhibit the PTT-induced inflammation through the laser-activated NO release in situ. This match of therapeutic agents and inhibitors not only achieves good therapeutic effects but also minimizes side effects as much as possible, which may provide an effective way for PTT-based treatment of atherosclerosis.

Purpose For the diagnosis of various diseases, simultaneous sensitive detection of multiple biomarkers using low sample volumes is needed. The purpose of the present research was to develop sensitive multiplex detection model of QD-based ELISA (QLISA), through the spectroscopic QD-analyte complex measurements in microvolume liquid droplets on a glass microslide. Methods QLISA was used for the detection of cartilage oligomeric matrix protein (COMP) and human growth hormone (hGH) as model analytes. The QLISA detection method included the formation of complexes consisting of analyte antigens, biotinylated antibodies and streptavidin-coated QDs. A specific immune-complex disassembling solution was used to dissociate analyte-antibody complexes from the bottom of the 96-well plate. After dissociation, the samples were diluted with PBS, and 2 µL transferred to a reusable glass slide for fluorescence (FL) scan. Results The alkaline immune-complex disassembling solution that most efficiently amplified QDs FL within a prolonged 17 h time was selected. Comparison of median fluorescence intensity (MFI) of 50 nM COMP, 25 nM COMP, and 5 nM COMP detection using QD655 with the dilution of the detached samples with PBS and without dilution resulted in significant MFI differences in all cases. The FL signal readouts from QD655 in the microvolume format were from 10 to 40 times stronger than those measured directly from a 96-well plate QLISAs. In duplex analysis, two analytes COMP and hGH were measured using different QD605 and QD525 in the same well. In the respectful 96-well plate QLISA format, two different analyte concentrations can be hardly distinguishable, but the transfer to micro-volumetric detection on the glass slide highly increased the signal strength according to green and red FL intensity of QDs. Conclusion Our method significantly enhances detection sensitivity, as compared to measured in parallel QLISAs in a 96 well plate format, enables multiplexing and may prove very valuable for samples of limited volumes.

Background Scar formation following large-area vaginal defects post-vaginoplasty is a major clinical challenge. Compared to skin scars, vaginal scars can lead to pain during intercourse and urinary difficulties, severely impacting quality of life. Small extracellular vesicles (sEVs) encapsulate diverse bioactive components, making them potential therapeutic agents. Designing functional scaffolds that incorporate sEVs is a promising approach for scarless vaginal defect repair. Methods sEVs-loaded scaffolds were developed through electrostatic interactions between negatively charged sEVs secreted by urine-derived stem cells (USC-sEVs) and positively charged human acellular amniotic membranes. The efficacy of sEVs-loaded scaffolds in the treatment of vaginal defects in rabbits was assessed by histological analysis. Immunofluorescence staining, Western blot, qRT-PCR and collagen gel contraction analyses were conducted to evaluate the antifibrotic effects of USC-sEVs. RNA sequencing was employed to elucidate the underlying mechanisms involved. LC‒MS/MS analysis was used to identify candidate upstream proteins in USC-sEVs. Results In vivo experiments demonstrated that the sEVs-loaded scaffolds promoted scarless healing of vaginal defects in rabbits by modulating collagen deposition, reducing fibrosis, and diminishing inflammation. In vitro experiments revealed that USC-sEVs significantly inhibited the proliferation, collagen production, and activation of fibroblasts with a fibrotic phenotype, indicating the antifibrotic properties of USC-sEVs. Transcriptome and Western blot analyses revealed that USC-sEVs treatment inhibited fibrosis by downregulating the TGF-β and p38 MAPK signaling pathways. LC‒MS/MS analysis identified 2653 proteins encapsulated in USC-sEVs. Western blot analysis revealed that decorin, an inhibitor of the TGF-β signaling pathway, and DUSP3, a negative regulator of p38 phosphorylation, were enriched in USC-sEVs and could be transferred to fibroblasts. Conclusion USC-sEVs inhibited fibrosis and promoted scarless healing by delivering decorin and DUSP3 proteins, which regulate the TGF-β and p38 MAPK signaling pathways, respectively. This study highlights the potential of sEVs-loaded scaffolds as a promising strategy for scarless vaginal repair following vaginoplasty, offering a novel approach for regenerative medicine with significant translational potential for clinical application.

Background A paramount issue in the realm of chronic wound healing among diabetic patients is the pervasive inflammatory response that persistently thwarts angiogenesis, thereby precipitating protracted delays in the healing process of such wounds. Employing zeolitic imidazolate framework-8 (ZIF-8) as a drug delivery platform, integrated within a temperature-sensitive injectable hydrogel, presents an intriguing strategy for the closure of various irregular wounds, modulation of inflammatory responses, and promotion of angiogenesis. Methods Herein, ZIF-8 loaded with curcumin (Cur) combined with methylcellulose/carboxymethyl chitosan (MCC) thermosensitive hydrogel was described. The assessment encompassed the temperature-sensitive properties, pH-responsive release, antimicrobial activity, and ROS scavenging capabilities of the MCC@ZIF-8@Cur hydrogel. A series of studies were conducted to explore its biocompatibility, pro-angiogenic effects, and macrophage M2 polarization induction. Additionally, a full-thickness skin defect model of diabetic rat was established to investigate the hydrogel’s multifaceted efficacy in facilitating wound repair, mitigating inflammatory responses, and fostering angiogenesis. Results The thermosensitive MCC@ZIF-8@Cur hydrogel possess the attribute of being injectable and capable of in situ formation (gelation temperature of ≥ 28 °C), thereby establishing an effective physical barrier for a multitude of irregular wound profiles. The incorporation of ZIF-8@Cur confers the hydrogel with exceptional antibacterial properties and the capability to eliminate reactive oxygen species (ROS). Moreover, the pH-responsive MCC@ZIF-8@Cur hydrogel continuously releases Cur and Zn²⁺, mitigating inflammation, inducing M2 polarization of macrophages, and promoting angiogenesis. This creates a favorable immune microenvironment conducive to skin regeneration, thereby accelerating the healing of diabetic wounds. In vivo studies have demonstrated a markedly accelerated wound healing ratio in rats within the hydrogel group compared to the Control group (p<0.001). By the 14th day of wound healing, the MCC@ZIF-8@Cur hydrogel group achieved a remarkable healing ratio of 97.22%, considerably surpassing the Control group (72.98%), showcasing remarkable potential for treating diabetic wounds. Conclusion The findings demonstrate the successful creation of a temperature-sensitive hydrogel that exhibits remarkable antibacterial properties and ROS scavenging capabilities. This hydrogel effectively suppresses inflammatory responses, modulates the polarization of macrophages towards the M2 phenotype, and promotes angiogenesis, thus fostering a favorable immune microenvironment for skin regeneration. These attributes collectively augur promising prospects and applications in the healing of diabetic wounds.

Purpose Metastatic non-small cell lung cancer (NSCLC) remains a global health threat, with patients facing inevitable disease progression despite standard-of-care therapy. Prior studies showed Platycodin D (PD)-induced cell cycle arrest and apoptosis in NSCLC via RNA regulatory network, yet elucidating PD’s mechanisms in NSCLC progression is challenging in the real world. Methods Biological effects of PD on NSCLC cell lines A549 and PC-9 were assessed through in vitro assays, encompassing apoptosis, proliferation, colony formation, migration and invasion. MicroRNAs (miRNAs) expression was profiled, and their roles were investigated using miRNA mimics or inhibitors. Predicted miRNA targets were validated via dual-luciferase reporter assays and Western blotting following bioinformatic prediction. PD’s metastatic inhibitory potential in NSCLC was evaluated in an in vivo lung cancer metastasis model. Furthermore, a homologous cell membrane-based PD delivery system was established to improve the biosafety and efficacy of PD in vivo. Results Hsa-miR-1246 was upregulated by PD treatment, and functional experiments demonstrated that the miR-1246-mimic enhanced PD’s suppressive effects on NSCLC cell proliferation, colony formation, migration, and invasion, while the miR-1246-inhibitor abrogated these effects. Notably, dual-luciferase assays confirmed that hsa-miR-1246 directly targeted the 3’ untranslated regions (3’ UTRs) of Fucosyltransferase 9 (FUT9), modulating its expression. Moreover, the hsa-miR-1246/FUT9 axis regulated the phosphorylation level and expression of GSK3β protein. In vivo, PD encapsulated in homologous cell membranes mitigated tumor growth and migration in metastatic NSCLC mice with minimal side effects. Conclusion The application of PD prompted an increase in the expression levels of hsa-miR-1246 and a concurrent decrease in FUT9. Importantly, the therapeutic efficacy of PD in vivo was markedly enhanced through homologous cell delivery system. Collectively, this study revealed the potential utility of PD in the treatment of NSCLC progression.

Purpose Acne is a serious disfiguring follicular sebaceous gland disorder that negatively affects patients’ quality of life and self-image. Chloramphenicol (CAM) is effective against Propionibacterium acnes and Staphylococcus aureus which cause acne, often used as a hospital preparation for acne treatment. However, because of its toxicity and poor water solubility, its use has been restricted. To overcome these limitations, the study focused on developing CAM-loaded binary ethosomes (CAM-BE) and incorporating them into a hydrogel system for transdermal delivery. Methods CAM-BE were prepared and characterized. Following incorporation of the selected formulation into the hydrogel, the formulation’s skin-interaction was evaluated using attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and confocal laser scanning microscopy (CLSM). Furthermore, a rat ear acne model was used to evaluate the formulation’s in vivo anti-inflammatory efficacy and ex vivo skin permeability. Results The optimal formulation contained ethanol/propylene glycol ratios of 3:7 (w/w), exhibited particle size was 97.68 ± 4.9 nm, zeta-potential was −23.5 ± 1.3 mV, and encapsulation efficiency was 60.36 ± 2.12%. The BE hydrogel that was created showed persistent drug release. Additionally, it demonstrated an enhanced flow of 4.374 ± 0.12 μg/cm²/hour, permeability coefficient was 3.65 ± 0.09 cm/h×10⁻³, and apparent skin deposition was 17.77 ± 1.13 μg/cm². CLSM and ATR-FTIR confirm that loading CAM into a binary ethosomes enables drugs to pass more easily through the stratum corneum. In vivo testing and histopathological analysis demonstrated that the CAM-BE hydrogel significantly inhibited swelling in the rat auricle, compared to both the free CAM hydrogel and adapalene hydrogel. Conclusion With their strong anti-inflammatory properties and improved skin penetration, binary ethosomes could be a viable new CAM delivery method. The new formulation was therefore seen as quite promising.

Purpose Circular RNAs (circRNAs) are associated with the progression of tumors and hold promise as potential biomarkers for liquid biopsy. Among these, the role of circPRMT5 in head and neck squamous cell carcinoma (HNSCC) remains to be elucidated. This study aims to examine the role and underlying mechanisms of circPRMT5 in the progression of HNSCC and to assess its potential diagnostic value in saliva exosomes. Methods The expression of circPRMT5 and its clinical significance in HNSCC were investigated. Both in vitro and in vivo studies were performed to elucidate the biological role of circPRMT5 in HNSCC. RNA sequencing was utilized to identify downstream mechanisms. To evaluate and validate these mechanisms, Western blotting, RNA-FISH, immunofluorescence, immunohistochemistry, RIP, and rescue experiments were employed. Finally, salivary exosomes were isolated, and the expression levels of circPRMT5 were assessed using qRT-PCR. Results The upregulation of circPRMT5 in HNSCC tissues was identified to be correlated with cervical lymph node metastasis and advanced clinical T stage. Both in vitro and in vivo experiments manifested that circPRMT5 promoted the proliferation and metastasis of HNSCC. Mechanistically, circPRMT5 was demonstrated to directly bind to and stabilize the insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), which, subsequently, binds to and stabilizes the serpin family E member 1 (SERPINE1) mRNA, thereby enhancing SERPINE1 expression. Furthermore, rescue experiments indicated that the proliferative, invasive, and migratory effects of circPRMT5 in HNSCC were dependent on the involvement of IGF2BP3 and SERPINE1. Notably, circPRMT5 levels were significantly elevated in the saliva exosomes of HNSCC patients, exhibiting substantial diagnostic value. Conclusion CircPRMT5 exhibits significant diagnostic utility through salivary exosomes and plays a crucial role in promoting the progression of HNSCC via the IGF2BP3-SERPINE1 pathway. These findings highlight the potential of circPRMT5 as a noninvasive diagnostic biomarker and a therapeutic target for patients with HNSCC.

Background and Aim Over the past years, noble metal-based nanoparticles have been extensively investigated for their applications in nanomedicine. However, there are still concerns about the potential adversities that these nanoparticles may present in an organism. In particular, whether they could cause an exacerbated cytotoxic response in susceptible tissues due to damage or disease, such as the heart, liver, spleen, or kidneys. In this regard, this study aims to evaluate the cytotoxicity of mono- and bimetallic nanoparticles of gold and silver (Au:Ag NPs) on healthy and hypertrophic cardiac H9c2 cells, and on healthy and metabolically activated macrophages derived from U937 cells. The main objective of this work is to explore the susceptibility of cells due to exposure to Au:Ag NPs in conditions representing cardiometabolic diseases. Methods Au:Ag NPs were synthesized in different molar ratios (Au:Ag, 100:0, 75:25, 50:50, 25:75, 0:100) using starch as a capping and reducing agent. Their physicochemical properties were characterized through UV-vis spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), ζ-potential measurements, and transmission electron microscopy (TEM). Moreover, the effect of the metal-based nanoparticle exposure on healthy and hypertrophic H9c2 cells was measured by analyzing the cellular vitality, the loss of mitochondrial membrane potential (∆Ψm), and the production of mitochondrial reactive oxygen species (mROS). Results The Au:Ag NPs did not affect the cell vitality of healthy or metabolically activated macrophages. On the contrary, healthy H9c2 cells showed decreased mitochondrial metabolism when exposed to NPs with higher Ag concentrations. Furthermore, hypertrophic H9c2 cells were more susceptible to the same NPs compared to their non-hypertrophic counterparts, and presented a pronounced loss of ∆Ψm. In addition, these NPs increased the production of mROS and regulated cell death in both cardiac cells. Conclusion In conclusion, low doses of high-Ag load in Au:Ag NPs produced cytotoxicity on H9c2 cardiac cells, with hypertrophic cells being more susceptible. These results suggest that cardiac hypertrophic conditions are more prone to a cytotoxic response in the presence of bimetallic Au:Ag NPs compared to healthy cells. In addition, this work opens the door to explore the nanotoxicity of noble metal-based NPs in biological disease conditions.

Purpose Most absorption enhancers boost the oral absorption of drugs via increasing intestinal permeability. However, they often damage intestinal mucosa and induce inflammatory reactions. The aim of this study is to synthesize a new absorption enhancer, punicic acid ethyl ester (PAEE), with excellent absorption-prompting effect and low toxicity. Methods The structure of PAEE was confirmed by NMR, MS, IR and UV. Setting oleic acid (OA) as the control, the three forms of punicic acid (PA), ie, free PA, PAEE, and pomegranate seed oil, in which PA exists in the form of triglyceride, were formulated into nanoemulsions (NE). The stability, physiochemical properties of the oils and NE were compared. The permeation-enhancing effect was estimated by phenol red intestinal transport experiments. The potential damage on small intestines was assessed by biochemical assay and pathological section. Results Though the three forms of PA had various strength in enhancing intestinal permeability, the difference was not significant (p > 0.05). Moreover, the effect was notably stronger than that of OA (p < 0.05) and was inversely related to the density and required HLB value of the oils. Compared to the corresponding oils, the NE exhibited much weaker effect in prompting intestinal permeability. Oral administration of OA and OA NE for 10 d impaired intestinal mucosa and villi along with strong inflammatory reactions in the small intestines. In contrast, the oils from PA series and their NE did not induce obvious intestinal inflammation. PAEE and its NE hindered the release of cytokines and increased the ratio of intestinal villus length to crypt depth. Conclusion PAEE is a promising absorption enhancer with a strong permeability-prompting effect and mucosa-protecting capacity against intestinal inflammation. It provides a practical strategy to enhance the bioavailability of the drugs with poor biological membrane penetration.

Kidney diseases are a significant global cause of death and disability, resulting from the destruction of kidney structure and function due to an imbalance between the death of renal parenchymal cells and the proliferation or recruitment of maladaptive cells, caused by various pathogenic factors. Currently, therapies and their efficacy for kidney diseases are limited. Ferroptosis is a newly discovered iron-dependent regulated cell death. The imbalance of iron homeostasis and lipid metabolism affects the occurrence and progression of kidney diseases by triggering ferroptosis, which is considered an important target for the development of kidney disease drugs. However, in clinical practice, targeted ferroptosis therapy for kidney diseases faces obstacles such as poor drug solubility, low drug resistance, and imprecise targeting. With the rapid development of nanomaterials in the medical field, new opportunities have emerged for the precise regulation of ferroptosis in the treatment of kidney diseases. This article provides a detailed introduction to the regulatory mechanisms of ferroptosis, the properties of nanomaterials, and their application in the treatment of kidney diseases, with a focus on discussing the mechanisms of action and therapeutic potential of nanomaterials based on ferroptosis regulation in kidney diseases. The aim of this article is to provide new ideas and directions for future kidney disease treatments.

Breast cancer is one of the most common types of cancer in women worldwide and is a leading cause of cancer deaths among women. As a result, various treatments have been developed to combat this disease. Breast cancer treatment varies based on its stage and type of pathology. Among the therapeutic options, ultrasound has been employed to assist in the treatment of breast cancer, including radiation therapy, chemotherapy, targeted immunotherapy, hormonal therapy, and, more recently, radiofrequency ablation for early-stage and inoperable patients. One notable advancement is ultrasound-targeted microbubble destruction (UTMD), which is gradually becoming a highly effective and non-invasive anti-tumor modality. This technique can enhance chemical, genetic, immune, and anti-vascular therapies through its physical and biological effects. Specifically, UTMD improves drug transfer efficiency and destroys tumor neovascularization while reducing toxic side effects on the body during tumor treatment. Given these developments, the application of ultrasound-assisted therapy to breast cancer has gained significant attention from research scholars. In this review, we will discuss the development of various therapeutic modalities for breast cancer and, importantly, highlight the application of ultrasound microbubble-targeted disruption techniques in breast cancer treatment.

Given the complexity of the central nervous system (CNS) and the diversity of neurological conditions, the increasing prevalence of neurological disorders poses a significant challenge to modern medicine. These disorders, ranging from neurodegenerative diseases to psychiatric conditions, not only impact individuals but also place a substantial burden on healthcare systems and society. A major obstacle in treating these conditions is the blood-brain barrier (BBB), which restricts the passage of therapeutic agents to the brain. Nanotechnology, particularly the use of nanoparticles (NPs), offers a promising solution to this challenge. NPs possess unique properties such as small size, large surface area, and modifiable surface characteristics, enabling them to cross the BBB and deliver drugs directly to the affected brain regions. This review focuses on the application of NPs in gene therapy and enzyme replacement therapy (ERT) for neurological disorders. Gene therapy involves altering or manipulating gene expression and can be enhanced by NPs designed to carry various genetic materials. Similarly, NPs can improve the efficacy of ERT for lysosomal storage disorders (LSDs) by facilitating enzyme delivery to the brain, overcoming issues like immunogenicity and instability. Taken together, this review explores the potential of NPs in revolutionizing treatment options for neurological disorders, highlighting their advantages and the future directions in this rapidly evolving field.

Tissue injury repair is a multifaceted and dynamic process characterized by complex interactions among various immune cells, with M2 macrophages assuming a crucial role. Exosomes derived from M2-type macrophages (M2-Exos) significantly influence the injury repair process through intercellular communication mediated by enriched microRNAs (miRNAs). This review aims to elucidate the biological processes underlying exosome formation, the synthesis and function of miRNAs, and the diverse methodologies employed for exosome extraction. Furthermore, we provide a comprehensive summary of the established multifarious functions and mechanisms of M2-Exos miRNAs in tissue injury repair across different systems, while also exploring their potential applications in disease prevention, diagnosis, and clinical practice. Despite the challenges encountered, the therapeutic use of M2-Exos in clinical contexts appears promising, prompting research efforts to focus on improving the efficiency of exosome extraction and application, as well as ensuring the safety of their clinical utilization.

Background Natural photosensitizers hold potential for photodynamic therapy (PDT) but are often limited by poor visible light absorption. Plant-derived exosome-like nanovesicles offer an innovative platform for enhancing photosensitizer performance. Methods Hypericum perforatum-derived nanovesicles (HPDENs) were characterized using electron microscopy, dynamic light scattering, and proteomic and miRNA sequencing. High-performance liquid chromatography confirmed hypericin content. PDT efficacy was assessed in vitro and in vivo. Results HPDENs exhibited robust photosensitizing properties, generating reactive oxygen species (ROS) through both Type I and Type II pathways upon light activation. In vitro, HPDENs showed light dose-dependent cytotoxicity against human melanoma cells, characterized by elevated ROS production and apoptosis induction. In vivo, HPDEN-mediated PDT significantly suppressed tumor growth and induced extensive tumor necrosis, with no observable toxicity to major organs. Conclusion HPDENs represent a novel plant-derived photosensitizer with dual ROS generation pathways and significant therapeutic efficacy, providing a promising platform for enhancing photodynamic therapy.