Journal of Nanobiotechnology最新文献

Background: Radiation-induced lung injury (RILI) is associated with alveolar epithelial cell death and secondary fibrosis in injured lung. Mesenchymal stem cell (MSC)-derived exosomes have regenerative effect against lung injury and the potential to intervene of RILI. However, their intervention efficacy is limited because they lack lung targeting characters and do not carry sufficient specific effectors. SARS-CoV-2 spike glycoprotein (SARS-CoV-2-S-RBD) binds angiotensin-converting enzyme 2 (ACE2) receptor and mediates interaction with host cells. MiR-486-5p is a multifunctional miRNA with angiogenic and antifibrotic potential and acts as an effector in MSC-derived exosomes. Ferroptosis is a form of cell death associated with radiation injury, its roles and mechanisms in RILI remain unclear. In this study, we developed an engineered MSC-derived exosomes with SARS-CoV-2-S-RBD- and miR-486-5p- modification and investigated their intervention effects on RIPF and action mechanisms via suppression of epithelial cell ferroptosis.

Results: Adenovirus-mediated gene modification led to miR-486-5p overexpression in human umbilical cord MSC exosomes (p < 0.05), thereby constructing miR-486-5p engineered MSC exosomes (miR-486-MSC-Exo). MiR-486-MSC-Exo promoted the proliferation and migration of irradiated mouse lung epithelial (MLE-12) cells in vitro and inhibited RILI in vivo (all p < 0.05). MiR-486-MSC-Exo suppressed ferroptosis in MLE-12 cells, and an in vitro assay revealed that the expression of fibrosis-related genes is up-regulated following ferroptosis (both p < 0.05). MiR-486-MSC-Exo reversed the up-regulated expression of fibrosis-related genes induced by TGF-β1 in vitro and improved pathological fibrosis in RIPF mice in vivo (all p < 0.05). SARS-CoV-2-S-RBD-modified and miR-486-5p-engineered MSC exosomes (miR-486-RBD-MSC-Exo) were also constructed, and the distribution of DiR dye-labeled miR-486-RBD-MSC-Exo in hACE2^CKI/CKI Sftpc-Cre⁺ mice demonstrated long-term retention in the lung (p < 0.05). MiR-486-RBD-MSC-Exo significantly improved the survival rate and pathological changes in hACE2^CKI/CKI Sftpc-Cre⁺ RIPF mice (all p < 0.05). Furthermore, miR-486-MSC-Exo exerted anti-fibrotic effects via targeted SMAD2 inhibition and Akt phosphorylation activation (p < 0.05).

Conclusions: Engineered MSC exosomes with SARS-CoV-2-S-RBD- and miR-486-5p-modification were developed. MiR-486-RBD-MSC-Exo suppressed ferroptosis and fibrosis of MLE-12 cells in vitro, and alleviated RILI and long-term RIPF in ACE2 humanized mice in vivo. MiR-486-MSC-Exo exerted anti-fibrotic effects via SMAD2 inhibition and Akt activation. This study provides a potential approach for RIPF intervention.

Abstrct: BACKGROUND: Apoptotic vesicles (ApoVs), which are extracellular vesicles released by apoptotic cells, have been reported to exhibit substantial therapeutic potential for inflammatory diseases and tissue regeneration. While extensive research has been dedicated to mesenchymal stem cells (MSCs), the investigation into immune cell-derived ApoVs remains limited, particularly regarding the function and fate of macrophage-derived ApoVs in the context of periodontitis (PD).

Results: Our study corroborates the occurrence and contribution of resident macrophage apoptosis in Porphyromonas gingivalis (Pg)-associated PD. The findings unveil the pivotal role played by apoptotic macrophages and their derived ApoVs in orchestrating periodontal bone remodeling. The enrichments of diverse functional miRNAs within these ApoVs are discerned through sequencing techniques. Moreover, our study elucidates that the macrophage-derived ApoVs predominantly deliver miR-143-3p, targeting insulin-like growth factor-binding protein 5 (IGFBP5), thereby disrupting periodontal bone homeostasis.

Conclusions: Our study reveals that macrophages in Pg-associated PD undergo apoptosis and generate miR-143-3p-enriched ApoVs to silence IGFBP5, resulting in the perturbation of osteogenic-osteoclastic balance and the ensuing periodontal bone destruction. Accordingly, interventions targeting miR-143-3p in macrophages or employment of apoptosis inhibitor Z-VAD hold promise as effective therapeutic strategies for the management of PD.

The primary issues in treating type 1 diabetes mellitus (T1DM) through the transplantation of healthy islets or islet β-cells are graft rejection and a lack of available donors. Currently, the majority of approaches use cell encapsulation technology and transplant replacement cells that can release insulin to address transplant rejection and donor shortages. However, existing encapsulation materials merely serve as carriers for islet cell growth. A new treatment approach for T1DM could be developed by creating a smart responsive material that encourages the formation of islet cell spheroids to replicate their 3D connections in vivo and controls the release of insulin aggregates. In this study, we used microfluidics to create thermally sensitive porous scaffolds made of poly(N-isopropyl acrylamide)/graphene oxide (PNIPAM/GO). The material was carefully shrunk under near-infrared light, enriched with mouse insulinoma pancreatic β cells (β-TC-6 cells), encapsulated, and cultivated to form 3D cell spheroids. The controlled contraction of the thermally responsive porous scaffold regulated insulin release from the spheroids, demonstrated using the glucose-stimulated insulin release assay (GSIS), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence assay. Eventually, implantation of the spheroids into C57BL/6 N diabetic mice enhanced the therapeutic effect, potentially offering a novel approach to the management of T1DM.

Ferroptosis has emerged as a promising strategy for cancer treatment. Nevertheless, the efficiency of ferroptosis-mediated therapy remains a challenge due to high glutathione (GSH) levels and insufficient endogenous hydrogen peroxide in the tumor microenvironment. Herein, we presented a nitric-oxide (NO) boost-GSH depletion strategy for enhanced ferroptosis therapy through a multifunctional nanoplatform with near-infrared (NIR) triggered NO release. The nanoplatform, IS@ATF, was designed that self-assembled by loading the NO donor L-arginine (L-Arg), ferroptosis inducer sorafenib (SRF), and indocyanine green (ICG) onto tannic acid (TA)-Fe³⁺‒metal-phenolic networks (MPNs) modified with hydroxyethyl starch. Inside the tumor, SRF could inhibit GSH biosynthesis, impair the activation of glutathione peroxidase 4, and disrupt the ferroptosis defensive system. In conjunction with TA-Fe³⁺‒MPNs, which has cascaded Fenton catalytic activity, it could navigate the lethal ferroptosis to cancer cells. Upon NIR laser irradiation, the ICG-generated ROS oxidated L-Arg to a substantial quantity of NO, which further depleted the intracellular GSH and caused LPO accumulation, enhancing cell ferroptosis. Moreover, ICG also serves as a photothermal agent that can produce hyperthermia when exposed to irradiation, further potentiating ferroptosis therapy. In addition, the nanoplatform showed significantly improved tumor therapeutic efficacy and anti-metastasis efficiency. This work thus demonstrated that utilizing NO boost-GSH depletion to enhance ferroptosis induction is a feasible and promising strategy for cancer treatment.

Nanobodies (Nbs) are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family as well as cartilaginous fish. Their unique structural and functional properties, such as their small size, the ability to be engineered for high antigen-binding affinity, stability under extreme conditions, and ease of production, have made them promising tools for diagnostics and therapeutics. This potential was realized in 2018 with the approval of caplacizumab, the world's first Nb-based drug. Currently, Nbs are being investigated in clinical trials for a broad range of treatments, including targeted therapies against PDL1 and Epidermal Growth Factor Receptor (EGFR), cardiovascular diseases, inflammatory conditions, and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. They are also being studied for their potential for detecting and imaging autoimmune conditions and infectious diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety of methods are now available to generate target-specific Nbs quickly and efficiently at low costs, increasing their accessibility. This article examines these diverse applications of Nbs and their promising roles. Only the most recent articles published in the last five years have been used to summarize the most advanced developments in the field.

Background: Osteoarthritis (OA) is a common joint disease that leads to chronic pain and functional limitations. Recent research has revealed soluble fibroblast activation protein (FAP) secreted from OA synovium could degrade type II collagen (Col2) in cartilage to promote the progression of OA. This study aimed to reveal the role of FAP from chondrocytes in OA and develop a novel lipid nanoparticle (LNP)-FAP siRNA delivery system for OA treatment.

Methods: The expression of FAP in the cartilage of knee OA patients was investigated using [68 Ga]Ga-FAPI-04 PET in vivo and immunofluorescence, western blotting, and RT-qPCR in vitro. Cell senescence was determined by senescence-associated β-galactosidase (SA-β-Gal) assay after FAP overexpressing or knockdown in chondrocytes. An OA model with chondrocyte-specific FAP knockout mice was applied to investigate the role of FAP in chondrocyte senescence and OA development. The therapeutic effects of lipid nanoparticle (LNP) @FAP siRNA on cartilage degeneration were evaluated in the rat OA model.

Results: Our study found that higher [68 Ga]Ga-FAPI-04 uptake was detected in knee OA patients by PET/CT scan. FAP mRNA and protein levels were highly expressed in OA-damaged cartilage. Moreover, we found that overexpression of FAP promotes chondrocyte senescence, and the genetic knockout of FAP in chondrocytes alleviates OA. Knockdown FAP by siRNA could alleviate chondrocyte senescence and suppress the NF-κB pathway to reduce the senescence-associated secretory phenotype (SASP). In the rat model of OA, intraarticular injection of LNP@FAP siRNA can reduce senescent cells and ameliorate cartilage destruction.

Conclusion: FAP-positive chondrocytes play a significant role in the pathogenesis of OA. Targeting these cells selectively has the potential to mitigate the progression of the disease. Our study provides valuable insights into the intraarticular injection of LNP@FAP siRNA as a promising strategy for the treatment of OA.

As the pathophysiological basis of type 2 diabetes mellitus (T2DM), insulin resistance (IR) is closely related to oxidative stress (OS) and inflammation, while nanozymes have a good therapeutic effect on inflammation and OS by scavenging reactive oxygen species (ROS). Hence, AuCePt porous hollow cascade nanozymes (AuCePt PHNs) are designed by integrating the dominant enzymatic activities of three metallic materials, which exhibit superior superoxide dismutase/catalase-like activities, and high drug loading capacity. In vitro experiments proved that AuCePt PHNs can ultra-efficiently scavenge endogenous and exogenous ROS. Moreover, AuCePt PHNs modified with lactobionic acid (LA) and loaded with disulfiram (DSF), named as AuCePt PHNs-LA@DSF, can significantly improve glucose uptake and glycogen synthesis in IR hepatocytes by regulating the insulin signaling pathways (IRS-1/AKT) and gluconeogenesis signaling pathways (FOXO-1/PEPCK). Intravenous administration of AuCePt PHNs-LA@DSF not only showed high liver targeting efficiency, but also reduced body weight and blood glucose and improved IR and lipid accumulation in high-fat diet-induced obese mice and diabetic ob/ob mice. This research elucidates the intrinsic activity of AuCePt PHNs for cascade scavenging of ROS, and reveals the potential effect of AuCePt PHNs-LA@DSF in T2DM treatment.

Global mortality data indicates cancer as the second-leading cause of death worldwide. Therefore, there's a pressing need to innovate effective treatments to address this significant medical and societal challenge. In recent years, X-ray-induced photodynamic therapy (X-PDT) has emerged as a promising advancement, revolutionizing traditional photodynamic therapy (PDT) for deeply entrenched malignancies by harnessing penetrating X-rays as external stimuli. Recent developments in X-ray photodynamic therapy have shown a trend toward minimizing radiation doses to remarkably low levels after the proof-of-concept demonstration. Early detection and real-time monitoring are crucial aspects of effective cancer treatment. Sophisticated X-ray imaging techniques have been enhanced by the introduction of X-ray luminescence nano-agents, alongside contrast nanomaterials based on X-ray attenuation. X-ray luminescence-based in vivo imaging offers excellent detection sensitivity and superior image quality in deep tissues at a reasonable cost, due to unhindered penetration and unimpeded auto-fluorescence of X-rays. This review emphasizes the significance of X-ray responsive theranostics, exploring their mechanism of action, feasibility, biocompatibility, and promising prospects in imaging-guided therapy for deep-seated tumors. Additionally, it discusses promising applications of X-PDT in treating breast cancer, liver cancer, lung cancer, skin cancer, and colorectal cancer.

Spinal cord injury (SCI) often accompanies impairment of motor function, yet there is currently no highly effective treatment method specifically for this condition. Oxidative stress and inflammation are pivotal factors contributing to severe neurological deficits after SCI. In this study, a type of curcumin (Cur) nanoparticle (HA-CurNPs) was developed to address this challenge by alleviating oxidative stress and inflammation. Through non-covalent interactions, curcumin (Cur) and poly (-)-epigallocatechin-3-gallate (pEGCG) are co-encapsulated within hyaluronic acid (HA), resulting in nanoparticles termed HA-CurNPs. These nanoparticles gradually release curcumin and pEGCG at the SCI site. The released pEGCG and curcumin not only scavenge reactive oxygen species (ROS) and prevents apoptosis, thereby improving the neuronal microenvironment, but also regulate CD74 to promote microglial polarization toward an M2 phenotype, and inhibits M1 polarization, thereby suppressing the inflammatory response and fostering neuronal regeneration. Moreover, in vivo experiments on SCI mice demonstrate that HA-CurNPs effectively protect neuronal cells and myelin, reduce glial scar formation, thereby facilitating the repair of damaged spinal cord tissues, restoring electrical signaling at the injury site, and improving motor functions. Overall, this study demonstrates that HA-CurNPs significantly reduce oxidative stress and inflammation following SCI, markedly improving motor function in SCI mice. This provides a promising therapeutic approach for the treatment of SCI.

Background: Animal and human health are seriously threatened by bacterial infections, which can lead to bacteremia and extremely high rates of morbidity and mortality. Recently, there have been reports indicating the involvement of exosomal circular RNAs (circRNAs) in a range of human disorders and tumor types. However, the role of exosomal circRNAs in bacterial infection remains elusive.

Methods: We extracted and identified exosomes from the culture medium of PIEC cells infected with or without Glaesserella parasuis. RNA sequencing analysis was performed on the exosomes to screen and identify circRNAs (circHIF1α) associated with Glaesserella parasuis infection. PIEC cells were infected with Staphylococcus aureus or Streptococcus suis 2 to further determine whether exosome-derived circHIF1α was the crucial circHIF1α associated with bacterial infections. The transmission process of exosomes and their circHIF1α between cells was clarified via exosome tracing and co-culture assay. Moreover, the mechanism of circHIF1α being packaged into exosomes was explored, and the effects of exosomes and their circHIF1α on cell proliferation, DNA damage and cell cycle were analyzed. In addition, the binding mode and site of interacting proteins with circHIF1α were further determined. In vivo and in vitro, the role of exosomes and their circHIF1α in host resistance to bacterial infection was confirmed.

Results: We first discovered a new circHIF1α that was very stable and detectable, encapsulated into exosomes by hnRNPA2B1, and whose expression in exosomes of bacterially infected PIEC cells significantly decreased. Additionally, exosomal circHIF1α reduced bacterial infection both in vitro and in vivo and suppressed the growth of reception cells. Mechanistically, the circHIF1α interacted with the KH domain of IGF2BP3 in an m6A-modified manner, which mediated DNA damage to arrest the cells at the G1/S phase through the interaction between the regulator of Chromosome Condensation 2 (RCC2) and γ-H2AX protein. Exosomal circHIF1α is a unique therapeutic target for bacterial infection since this work highlights its critical function in fighting bacterial infection.