International Journal of Nanomedicine最新文献

Objective: Radioimmunotherapy (RIT) is a promising treatment for deep-seated and metastatic tumors, but its efficacy is limited by the immunosuppressive tumor microenvironment (TME) and a narrow therapeutic window. This study aimed to develop a novel nanoplatform to overcome these constraints by simultaneously sensitizing tumors to radiation, inducing cuproptosis, and reprogramming the immunosuppressive TME.

Methods: We engineered a PEGylated copper-loaded black phosphorus nanoplatform (BPNS@Cu-PEG). Its functionality as a radiosensitizer and cuproptosis inducer was evaluated. The mechanisms of TME reprogramming were investigated, including glutathione (GSH) depletion, reactive oxygen species (ROS) amplification, hypoxia alleviation, and M2-to-M1 macrophage repolarization. Furthermore, we systematically evaluated its antitumor immune effects in vitro and in vivo.

Results: BPNS@Cu-PEG was synthesized with a high copper incorporation rate of 93%. In vitro cellular assays confirmed that the internalized nanoplatform effectively induced cuproptosis and immunogenic cell death (ICD) while simultaneously regulating the TME. In vivo, BPNS@Cu-PEG not only potently inhibited tumor progression and stimulated robust antitumor immunity under low-dose radiotherapy but also exhibited an excellent safety profile.

Conclusion: This work establishes a copper-based, low-dose radioimmunotherapy strategy. The BPNS@Cu-PEG nanoplatform presents a viable and potent strategy to counteract radioresistance and promote systemic antitumor immunity, potentially broadening the therapeutic application and safety profile of RIT.

Gliomas are the most prevalent Central Nervous System (CNS) tumors. Among them, glioblastoma (grade IV) is the most challenging brain cancer because of its highly aggressive nature, treatment resistance and poor prognosis. Matrix metalloproteinase (MMP) is a family of zinc-dependent protein hydrolases. In recent years, MMPs have become a research focus owing to their central role in tumor microenvironment remodeling, angiogenesis, invasion, metastasis. Clinical studies have shown that the expression levels of MMPs in glioma tissues exhibit a significant positive correlation with the degree of malignancy and aggressiveness of gliomas. Therefore, the idea of MMPs as a detection target and therapeutic target can be proposed. Nanoparticle drug delivery system, as a cutting-edge technology, has shown great potential and broad prospects in clinical applications. The system realizes the targeted delivery, sustained-release control and bioavailability of drugs, and provides new ideas and means for the management of various pathological conditions. In this review, we will comprehensively discuss the expression relationship and major regulatory mechanisms between MMPs and gliomas, the composition of nano-drug delivery systems, routes of administration, and common types of nanomaterials used for the treatment of gliomas. In addition, we focus on cell-penetrating peptides (CPPs) as an entry point. We summarize the common kinds of activatable CPPs and how they are applied in nano-drug delivery systems. It is also found that MMP-responsive systems, which can be used for the treatment of gliomas, can activate CPPs, and through the synergistic effect between CPPs and MMPs, MMPs can be used as detection or therapeutic targets and combined with nano-drug delivery system for the medical management of gliomas. The nano-drug delivery system can demonstrate exceptional blood-brain barrier (BBB) penetration efficiency and precisely target the glioma region to release the drug. This delivery approach may prove to be beneficial for glioma patients.

This review highlights the potential of muco-adhesive hydrogel-based exosome delivery vehicles for the regeneration of periodontal tissue and the reduction of inflammation in periodontitis. Exosomes, mainly produced from mesenchymal stem cells (MSCs), represent nano-sized vesicles loaded with bioactive molecules that can stimulate tissue repair and modulate inflammatory pathways. The review provides a thorough view for the synthesis of the in vitro, in vivo and clinical-pilot studies on exosome-loaded muco-adhesive hydrogels, encompassing the physicochemical characterization, exosome delivery and biological efficacies. In vitro studies highlight the regenerative potential of exosomes on periodontal ligament cells and on alveolar bone cells. In vivo animal models have shown significant improvements in tissue regeneration with effective inflammation control. Preliminary clinical pilot studies similarly show promising results for periodontal tissue healing. The use of exons in combination with muco-adhesive hydrogels provides an effective and non-invasive approach for the targeted, prolonged therapeutic delivery for the treatment of periodontal disease. The main conclusion of this review is that exosome loaded muco-adhesive hydrogels represent a promising strategy for developing strategies to treat periodontitis, setting up as its double aims to enhance the regeneration of tissues and reduce inflammation.

Neutrophils, a key component of the innate immune system, play a crucial role in immune responses. In 2004, Brinkmann et al identified neutrophil extracellular traps (NETs) as a novel antibacterial mechanism. However, NETs have since been implicated in the pathogenesis of various diseases, including autoimmune disorders, sepsis, and cancer. Consequently, targeting NETs has emerged as a promising therapeutic approach. Mesenchymal stem cells (MSCs) have demonstrated efficacy in modulating NET formation, but MSC-derived exosomes offer distinct advantages over whole MSCs due to their lower immunogenicity, higher biological stability, and ability to deliver bioactive molecules like miRNAs and CD59. These exosomes can block critical signaling pathways involved in NET formation and protect neutrophil mitochondria, inhibiting NET release. Despite challenges such as low yield and targeting efficiency, ongoing research has made significant strides in addressing these issues. This article reviews the current progress in MSC-derived exosome-based anti-NET therapies and discusses potential strategies to enhance their therapeutic application.

Osteoporosis (OP) is a common bone disease that involves low bone mass and high risk of fracture mainly in older men and women and perimenopausal years. Although conventional therapies provide good therapeutic effects, they have numerous limitations, including poorly targeted and systemic administration and severe side effects. Recent developments in nanotechnology enabled design of enzyme-immobilized nanocarriers as experimental platforms to enhance the delivery of therapeutic agents to bone tissue. This review pays special attention to the development of these multifunctional systems that can transport anti-osteoporotic agents and carry enzymes to stimulate bone formation. Enzymes like alkaline phosphatase for mineralization, superoxide dismutase for reactive oxygen species reduction, and cathepsin K inhibitors for osteoclast regulation are highlighted to demonstrate rationale behind enzyme immobilization. Enzyme immobilization promotes local bone regeneration by increasing enzyme stability and activity at target site offering more sustained therapeutic effect in OP therapy. Polymeric NP and liposomes like nanocarriers are well explained along with their various mechanisms such as stability, bioavailability controlling and release kinetics. Further, we review the current literature for the recent in vivo and in vitro studies highlighting the potential of these systems in stimulating osteoblast function and suppressing osteoclast-mediated bone resorption. Areas for future research include improving carrier design for increased targetability and exploring the clinical translation of these nanocarrier systems for OP management.

With the ongoing trend of population aging worldwide, the incidence of Alzheimer's disease (AD) is steadily increasing. In the absence of effective therapeutic options for atypical forms of AD, reducing its prevalence and improving treatment outcomes have become pressing priorities. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have attracted growing attention as a new cell-free therapeutic approach for AD due to their high stability, low immunogenicity, and minimal tumorigenic risk. This review provides a comprehensive overview of the pathological mechanisms underlying AD, highlights the diagnostic potential of MSC-EVs, and elaborates on their therapeutic advantages and mechanisms of action. Furthermore, it addresses the key challenges and considerations associated with the clinical translation of MSC-EVs.

Purpose: While reprogramming tumor-associated macrophages (TAMs) using cytokines shows promise for cancer therapy, its clinical translation is limited by poor bioavailability. Essential mineral selenium (Se), via selenoproteins, is crucial for innate immunity and adaptive immunity regulation.

Methods: Addressing the need for safer, more effective methods to enhance macrophage function, we leveraged the essential mineral Se to create gluconic acid-coated Se nanoparticles (GA-SeNPs). The in vivo efficacy of GA-SeNPs was assessed via intratumoral injection in a B16-F10 melanoma BALB/c mouse model, mirroring the administration route of the first virotherapy for advanced melanoma.

Results: These nanoparticles successfully induced M2-to-M1 macrophage repolarization and inhibited cancer cell growth through reactive oxygen species (ROS) generation. We confirmed through transcriptomic analysis that GA-SeNPs influence the genes of key components in the biosynthesis of selenoproteins. Additionally, GA-SeNPs influence oxidative phosphorylation, inflammatory, and ribosome pathways by promoting the shift of M2 macrophages to an M1 phenotype. Crucially, in a melanoma mouse model, GA-SeNPs treatment yielded a >4-fold tumor weight reduction and effectively repolarized TAMs to an M1 phenotype while maintaining TAMs levels. GA-SeNPs inhibit cancer growth in vivo by disrupting the immunosuppressive tumor microenvironment. They maintain total TAM counts while strongly promoting M2-to-M1 repolarization.

Conclusion: Their dual localization within both TAMs and cancer cells further highlights their therapeutic potential, presenting a promising strategy to advance TAM-based cancer therapies and improve clinical outcomes.

Background: The treatment of osteoarticular tuberculosis (TB) remains a significant clinical challenge, primarily due to inadequate drug delivery to bone tissues, severe bone destruction, and delayed repair processes. Conventional pharmacological therapy has limited efficacy and often necessitates surgical intervention. Thus, we developed a bone-targeted nanosystem by integrating rifapentine (RPT) and alendronate (ALN) to improve drug delivery, mitigate TB-induced bone destruction, and facilitate bone regeneration.

Methods: In this study, ALN was conjugated to PLGA-PEG-COOH utilizing the DCC/NHS method and subsequently loaded with RPT through premix membrane emulsification, resulting in the formation of the RPT/ALN-PLGA-PEG nanosystems. The physicochemical properties of the nanosystems were characterized, and its antibacterial activity, cytotoxicity, and impact on osteogenic/osteoclastic differentiation were evaluated in vitro. Bone-targeting efficacy and biodistribution were assessed using in vivo experiments. A rabbit spinal TB model was used to assess therapeutic efficacy based on inflammatory and bone turnover markers, bone mineral density (BMD), and histopathological analyses.

Results: The RPT/ALN-PLGA-PEG nanosystems exhibited a uniform size of 89 nm, excellent stability, and sustained drug-release characteristics. In vitro, the nanosystems demonstrated excellent antibacterial activity, low cytotoxicity, and the ability to suppress osteoclastogenesis while promoting osteoblast differentiation. In vivo imaging and tissue distribution studies have demonstrated that the RPT/ALN-PLGA-PEG nanosystem achieved a drug concentration in bone tissue at least 3-fold higher than that of the non-targeted nanosystem. In vivo, the bone-targeted nanosystem effectively alleviated inflammation, stabilized levels of bone resorption markers, and improved BMD, accompanied by elevated levels of osteogenic markers. Histological scores revealed complete bone regeneration in the RPT/ALN-PLGA-PEG group, whereas fibrous tissue formation was observed in the other groups.

Conclusion: The RPT/ALN-PLGA-PEG nanosystems demonstrated remarkable bone-targeting capability, sustained and potent antibacterial efficacy, and mitigation of bone destruction, coupled with the promotion of bone repair. These findings provide an innovative approach for addressing osteoarticular TB.

Background: Os draconis (OD), a traditional Chinese medicine from fossil mammalian bones, effectively treats insomnia and anxiety. Its usage conflicts with the laws, causing a shortage. This research clarifies OD's pharmacodynamic mechanisms, aiming to establish a scientific basis for developing novel artificial substitutes.

Methods: This research used a mouse chronic insomnia paradigm to assess an os draconis decoction (DOD). DOD was digested in vitro, and the resultant nanoparticles (OD-NPs) were analyzed by scanning electron microscopy, dynamic light scattering, X-ray diffraction, and Fourier transform infrared spectroscopy. The in vivo effects were evaluated using behavioral tests, Nissl staining, neuronal activity in the nucleus tractus solitarii (NTS), and plasma 5-HT levels. In vitro mechanistic investigations used FITC-labeled OD-NPs to detect cellular uptake. The research used calcium channel blockers to examine changes in intracellular Ca²⁺ concentration and critical protein expression in 5-HT-related pathways.

Results: After DOD treatment, significantly improved movement in the Open field, brain malondialdehyde (MDA) and plasma tumor necrosis factor-α (TNF-α) were reduced, increased hippocampal Nissl bodies, and alleviated neuronal damage. Digested DOD formed numerous sub-1000 nm spindle particles. Its composition remained carbonate hydroxyapatite (F-rich), but crystallinity decreased. DOD elevated plasma 5-HT and c-fos expression in the NTS. In vitro, OD-NPs were uptaken by cells, increasing supernatant 5-HT and cytosolic calcium. This upregulated TPH1 and DdC expression, a trend unaffected by Ca²⁺ channel blockade, unlike the filtrate group.

Conclusion: This is the first research to suggest that oral DOD is digested into OD-NPs, which are then internalized by enterochromaffin cells. This absorption initiates calcium signaling, boosts 5-HT release, and then activates the vagus nerve-NTS pathway, thereby regulating central nervous system activity. This research provides scientific proof for the clinical application of OD, lays the groundwork for the development of artificial alternatives, and generates ideas for future traditional Chinese medicine research.

Purpose: The present study aimed to systematically compare the in vitro and in vivo characteristics of three nano-assemblies with different components derived from Shaoyao Gancao Decoction (SGD), with particular emphasis on their differential effects on oral absorption of paeoniflorin (Pae).

Methods: The self-assembled nanoparticles of SGD (SGD-SAN), glycyrrhizic acid self-assembled nanomicelles (GL-SNM), and Glycyrrhiza protein self-assembled nanoparticles (GP-SAN) were separated or prepared, and characterized in terms of particle size, zeta potential, morphology, drug loading, and in vitro release behavior. The single-pass intestinal perfusion and pharmacokinetic studies of SGD-SAN, GL-SNM, and GP-SAN following oral administration were performed to evaluate their absorption-enhancing effect. Chemical interference agents (NaCl, urea, and Tween 20) were added, followed by particle size detection, to identify the types of intermolecular forces in the self-assemblies.

Results: Three nano-assemblies exhibited significant differences in particle size (133 nm for SGD-SAN, 154 nm for GL-SNM, and 184 nm for GP-SAN) and drug loading (5.54% for SGD-SAN, 10.70% for Pae GL-SNM, and 21.52% for Pae GP-SAN). While hydrophobic interactions act as the common core force driving the formation of all nano-assemblies, their dependencies on other intermolecular forces vary remarkably. SGD-SAN, GL-SNM, and GP-SAN exhibited sustained Pae release (50-75% over 12 h vs 100% for the Pae solution in 2 h). In situ intestinal perfusion in rats showed significantly higher effective permeability coefficients (P_eff ) for all nano-assemblies than the Pae solution, with GP-SAN exhibiting the highest ileal absorption, which may be attributed to preferential M-cell uptake facilitated by its protein-rich composition. Pharmacokinetic studies confirmed superior performance of GP-SAN with the highest AUC_0-t (11209.01 ± 2093.72 ng/mL·h) and C_max (2896.04 ± 255.01 ng/mL), representing 2.0-fold and 3.0-fold increases over Pae solution (5676.14 ± 311.61 ng/mL·h & 964.89 ± 128.81 ng/mL), respectively. GL-SNM and SGD-SAN also significantly enhanced the bioavailability (AUC_0-t increased by 65% and 45%, respectively).

Conclusion: These results suggested that nano-assemblies, particularly protein-based GP-SAN, provide a structural foundation for SGD's bioavailability-enhancing effect.