Journal of Nanobiotechnology最新文献

Background: Pathological scars (PS) are one of the most common complications in patients with trauma and burns, leading to functional impairments and aesthetic concerns. Mechanical tension at injury sites is a crucial factor in PS formation. However, the precise mechanisms remain unclear due to the lack of reliable animal models.

Results: We developed a novel mouse model, the Retroflex Scar Model (RSM), which induces PS by applying controlled tension to wounds in vivo. RNA sequencing identified significant transcriptome changes in RSM-induced scars. Elevated expression of E-Selectin (Sele) was observed in endothelial cells from both the RSM model and human PS (Keloid) samples. In vitro studies demonstrated that cyclic mechanical stretching (CMS) increased Sele expression, promoting monocyte adhesion and the release of pro-inflammatory factors. Single-cell sequencing analysis from the GEO database, complemented by Western blotting, immunofluorescence, and co-immunoprecipitation, confirmed the role of Sele-mediated monocyte adhesion in PS formation. Additionally, we developed Sele-targeted siRNA liposome nanoparticles (LNPs) to inhibit monocyte adhesion. Intradermal administration of these LNPs effectively reduced PS formation in both in vivo and in vitro studies.

Conclusions: This study successfully established a reliable mouse model for PS, highlighting the significant roles of mechanical tension and chronic inflammation in PS formation. We identified Sele as a key therapeutic target and developed Sele-targeted siRNA LNPs, which demonstrated potential as a preventive strategy for PS. These findings provide valuable insights into PS pathogenesis and open new avenues for developing effective treatments for pathological scars.

Radiotherapy (RT) stands as a frontline treatment modality in clinical breast oncology, yet challenges like ROS reduction, high toxicity, non-selectivity, and hypoxia hinder efficacy. Additionally, RT administered at different doses can induce varying degrees of radioimmunotherapy. High doses of radiation (>10 Gy) may result in immune suppression, while moderate doses (4-10 Gy), although capable of mitigating the immune suppression caused by high-dose radiation, are often insufficient in effectively killing tumor cells. Therefore, enhancing the generation of ROS and ameliorating the tumor hypoxic immune-suppressive microenvironment at moderate radiation doses could potentially drive radiation-induced immune responses, offering a fundamental solution to the limitations of RT. In this study, a novel multifunctional nanoplatform, RMLF, integrating a Ru (II) complex into folate-functionalized liposomes with BSA-MnO₂ nanoparticles was proposed. Orthogonal experimental optimization enhances radiosensitization via increasing accumulation in cancer cells, elevating ROS, and contributing to a dual enhancement of the cGAS-STING-dependent type I IFN signaling pathway, aimed to overcome the insufficient DAMPs typically seen in the conventional RT at 4 Gy. Such a strategy effectively activated cytotoxic T lymphocytes for infiltration into tumor tissues and promoted the polarization of tumor-associated macrophages from the M2 to M1 phenotype, substantially bolstering immune memory responses. This pioneering approach represents the first use of a ruthenium complex in radioimmunotherapy, activating the cGAS-STING pathway to amplify immune responses, overcome RT resistance, and extend immunotherapeutic potential.

The tumor microenvironment (TME) is a complex system characterized by low oxygen, low pH, high pressure, and numerous growth factors and protein hydrolases that regulate a wide range of biological behaviors in the tumor and have a profound impact on cancer progression. Immunotherapy is an innovative approach to cancer treatment that activates the immune system, resulting in the spontaneous killing of tumor cells. However, the therapeutic efficacy of these clinically approved cancer immunotherapies (e.g., immune checkpoint blocker (ICB) therapies and chimeric antigen receptor (CAR) T-cell therapies) is far from satisfactory due to the presence of immunosuppressive TMEs created in part by tumor hypoxia, acidity, high levels of reactive oxygen species (ROS), and a dense extracellular matrix (ECM). With continuous advances in materials science and drug-delivery technologies, biomaterials hold considerable potential for targeting the TME. This article reviews the advances in biomaterial-based targeting of the TME to advance our current understanding on the role of biomaterials in enhancing tumor immunity. In addition, the strategies for remodeling the TME offer enticing advantages; however, the represent a double-edged sword. In the process of reshaping the TME, the risk of tumor growth, infiltration, and distant metastasis may increase.

Amidst the burgeoning field of cancer nanomedicine, dense extracellular matrices and anomalous vascular structures in the tumor microenvironment (TME) present substantial physical barriers to effective therapeutic delivery. These physical barriers hinder the optimal bioavailability of nanomedicine. Here, we propose a pioneering dual-modal strategy for overcoming physical barriers via soft organosilica nanocapsules (SMONs). Hyaluronidase-modified flexible spheres work by degrading the extracellular matrix and utilizing their flexible characteristics to enhance penetration into deeper layers. Compared with their stiff counterparts, the SMONs show diminished Young's modulus, then the inherent softness of the SMONs confers distinct advantages, and significantly augmented cellular internalization within 4T1 cells, leading to an amplified in vitro photodynamic therapeutic effect. Furthermore, hyaluronidase-functionalized SMONs (SMONs-HAase) exhibit enhanced tumor penetration in 3D spheroids. Post incorporation of the photosensitizer chlorin e6, when administered intravenously, these soft organosilica nanocapsules amplify the efficacy of photodynamic therapy. In addition, RNA-seq analysis of SMONs-HAase-Ce6 shows it alters gene expression, degrading the extracellular matrix and impairing mitochondrial function. To sum up, this work elucidates the potential of a dual-modal strategy, highlighting the promise of SMONs in overcoming TME physical barriers and optimizing therapeutic outcomes.

Background: Migratory insect infestation caused by Sogatella furcifera is a serious threat to rice production. The most effective method available for S. furcifera control is intensive insecticide spraying, which cause widespread resistance. RNA interference (RNAi) insecticides hold enormous potential in managing pest resistance. However, the instability and the poor efficiency of cross-kingdom RNA trafficking are key obstacles for the application in agricultural pest management.

Methods: We present dendritic mesoporous silica nanoparticles (DMSNs)-based nanocarrier for delivering siRNA and nitenpyram to inhibit the metabolic detoxification and development of S. furcifera, thereby preventing its proliferation.

Results: This nano complex (denoted as N@UK-siRNA/DMSNs) significantly enhanced the stability of siRNA (efficacy lasting 21 days) and released cargos in GSH or planthopper bodily fluid with a maximum release rate of 84.99%. Moreover, the released UK-siRNA targeting two transcription factors (Ultraspiracle and Krüppel-homolog 1) downregulated the developmental genes Ultraspiracle (0.09-fold) and Krüppel-homolog 1 (0.284-fold), and downstream detoxification genes ABC SfABCH4 (0.016-fold) and P450 CYP6FJ3 (0.367-fold).

Conclusion: The N@UK-siRNA/DMSNs inhibited pest development and detoxification, significantly enhancing susceptibility to nitenpyram to nanogram level (LC₅₀ is 250-252 ng/mL), resulting in a 5.37-7.13-fold synergistic ratio. This work proposes a comprehensive management strategy for controlling S. furcifera to ensure the green and safe production of rice.

Background: Recent years, exosomes have been increasing used to treat diseases, but there is little research on how exosomes affect the metabolism of the body after entering. Therefore, in this study, we discussed the changes of metabolic spectrum and determined the differentially expressed metabolites in the serum of cynomolgus monkeys after injecting exosomes. Six cynomolgus monkeys were divided into control group and exosomes group. After intravenous injection of exosomes, the peripheral blood serum of cynomolgus monkeys was collected at baseline, day 1, day 7 and day 14 respectively. An ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based non-targeted metabolomics platform was used to detect the metabolites. The metabolic spectra of two groups of cynomolgus monkeys were identified and compared, and the time series changes of metabolites in exosomes were described.

Results: The results showed that there was significant difference in metabolic spectrum between the two groups. 45, 114, 49, 39 differentially expressed metabolites were identified in baseline, day 1, day 7, and day 14, respectively. 6-hydroxydopamine, a metabolite related to the regulation of nerve function, was also found. Tryptophan metabolism, choline metabolism in cancer, porphyrin and chlorophyll metabolism were involved in day 1. Sphingolipid metabolism and histidine metabolism were involved in day 7. Three pathways, including choline metabolism, sphingolipid metabolism and biotin metabolism in cancer were involved in day 14. Through time series analysis, it was found that the level of propionylcarnitine and biliverdin increased on day 1 after inoculation with exosomes, while the level of hippuric acid decreased. These changes of immune-related metabolites suggested that exosomes might participate in the immunoregulation reaction after entering the body of cynomolgus monkeys.

Conclusions: In our current study, we found that exosomes injected intravenously affect the changes of metabolites and metabolic pathways in cynomolgus monkeys. Intravenous injection of exosomes may affect the metabolite 6-hydroxydopamine, sphingolipid metabolic pathway, and choline metabolic in cancer pathway, which is of some significance for the treatment of Parkinson's disease. In addition, exosomes may also affect the immune-related metabolites in vivo, such as propionylcarnitine, biliverdin, hippuric acid metabolites, as well as tryptophan metabolism pathway, sphingolipid metabolism pathway involved in immune regulation, which is of great significance for the future study of immune-regulatory mechanisms of exosomes.

Oxidative stress (OS) and neuroinflammation are critical pathological processes in secondary brain injury (SBI) after intracerebral hemorrhage(ICH), and their intimate interactions initiate and aggravate brain damage. Thus, targeting oxidative stress and neuroinflammation could be a promising therapeutic strategy for ICH treatment. Here, we report a high-performance platform using polydopamine (PDA)-coated diselenide bridged mesoporous silica nanoparticle (PDA-DSeMSN) as a smart ROS scavenger and ROS-responsive drug delivery system. Caffeic acid phenethyl ester (CAPE) was blocked in the pore of DSeMSN by covering the pore with PDA as a gatekeeper. PDA-DSeMSN @CAPE maintained high stability and underwent reactive oxygen species (ROS)-responsive degradation and drug release. The intelligent nanomaterial effectively eliminated ROS, promoted M1 to M2 microglial conversion and suppressed neuroinflammation in vitro and in vivo. Importantly, intravenous administration of PDA-DSeMSN@CAPE specifically accumulated in perihematomal sites and demonstrated robust neuroprotection in an ICH mouse model with high biological safety. Taking together, the synergistic effect of ROS-responsive drug delivery ability and ROS scavenging ability of PDA-DSeMSN makes it a powerful drug delivery platform and provided new considerations into the therapeutic action to improve ICH-induce brain injury.

Background: Acute lung injury (ALI) triggers the activation of pulmonary macrophages, which in turn produce excessive amounts of reactive oxygen species (ROS).

Results: We synthesized ROS-responsive red light-emitting carbon dots (RCMNs) that target lung macrophages, possess bioimaging capabilities, and efficiently eliminate intracellular ROS, thereby demonstrating anti-inflammatory effects for treating acute lung injury (ALI). In an LPS-induced ALI mouse model, RCMNs showed bioimaging and therapeutic potential, reducing lung damage and inflammation by targeting ROS-damaged tissue. RCMNs also improved alveolar macrophage activity, decreased inflammatory cytokines (TNF-α and IL-6), and enhanced survival in endotoxic shock, indicating their therapeutic potential for ALI. RNA-seq analysis revealed that RCMNs modulate signaling pathways related to calcium, TNF, and Toll-like receptors, highlighting their role in regulating inflammation and immune responses. Mechanistically, RCMNs alleviate inflammation in ALI by enhancing mitochondrial function in lung macrophages, as evidenced by improved mitochondrial morphology and membrane potential.

Conclusions: This protective effect is mediated through the regulation of intracellular Ca²⁺ levels and mitochondrial respiratory chain complexes, suggesting RCMNs as a therapeutic strategy for mitochondrial dysfunction in ALI.

Background: Probiotics can colonize both the human and animal bodies and consist of active microorganisms that are beneficial to health. The use of probiotics has been shown to alleviate certain neurological diseases and disturbances in gut microbiota resulting from chronic ethanol exposure. Research indicates that probiotics can influence the nervous system via the microbial-gut-brain axis, wherein extracellular vesicles secreted by the gut microbiota play a significant role in this process.

Results: In this study, we first established a 30-day ethanol exposure and probiotic gavage mouse model, both of which influenced behavior and the composition of gut microbiota. We then extracted gut microbiota-derived extracellular vesicles from the feces of these model mice and injected them into new mice via the tail vein to assess the role of each set of extracellular vesicles. The results indicated that the extracellular vesicles derived from the intestinal microbiota in the ethanol group induced anxiety-like behavior and hippocampal neuroinflammation in the recipient mice. In contrast, the extracellular vesicles secreted by the gut microbiota from the probiotic group mitigated the anxiety-like behavior and neuroinflammation induced by ethanol-influenced extracellular vesicles.

Conclusions: Our study demonstrates that extracellular vesicles secreted by the gut microbiota can influence the nervous system via the microbial-gut-brain axis. Furthermore, we found that the extracellular vesicles secreted by the gut microbiota from the probiotic group exert a beneficial therapeutic effect on anxiety and hippocampal neuroinflammation.

Radionuclide therapy (RT) is widely used to advanced local cancers. However, its therapeutic efficacy is limited to the radiation resistance of cancer cells. Combination therapy aims to circumvent tumor resistance, and the combination of RT with photothermal therapy (PTT), photodynamic therapy (PDT), chemotherapy (CMT), and immunotherapy has shown promising treatment outcomes. Nanotechnology holds promise in advancing combination therapy by integrating multiple therapies on a nanostructure platform. This is due to the increased surface area, passive/active targeting capabilities, high payload capacity, and enriched surface of nanomedicines, offering significant advantages in treatment sensitivity and specificity. In the first part of this review, we categorize radionuclide therapy. The second part summarizes the latest developments in combination therapies, specifically focusing on the integration of RT with PTT, PDT, CMT and immunotherapy. The last part provides an overview of the challenges and potential opportunities related to radionuclide-labelled nanoparticles for cancer combination therapy.