Journal of Nanobiotechnology最新文献

Background: The glycocalyx serves as the skeletal structure of the outer layer of endothelial cells and regulates the function of endothelial cells. Porphyromonas gingivalis (P. gingivalis) outer membrane vesicles (OMVs) exhibit the fundamental biological traits of bacteria, such as inducing inflammatory responses, damaging host cells, and delivering virulence factors to distal tissues like the cardiovascular system. This study aimed to investigate the role of P. gingivalis OMVs in vascular endothelial glycocalyx injury.

Methods: In this clinical study, serum levels of syndecan-1 (SDC1) and heparan sulfate (HS), biomarkers of endothelial glycocalyx injury, were measured and compared between patients with stage III-IV periodontitis and those with stage I-II or no periodontitis. Then, glycocalyx injury was detected using transmission electron microscopy, immunofluorescence and western blotting after vascular endothelial cells were stimulated and C57BL/6J mice were administered with P. gingivalis OMVs via tail vein injection. Transcriptomic high-throughput sequencing analysis and in vitro and in vivo rescue experiments were conducted to determine the key mechanism in glycocalyx injury. Experiments were conducted using OMVs, ^PPAD-OEOMVs, and ^ΔPPADOMVs to identify the special virulence factors in OMVs.

Results: This study revealed that serum levels of SDC1 and HS were significantly higher in patients with stage III-IV periodontitis (P < 0.05). A marked reduction in both the fluorescence intensity of the glycocalyx and the expression levels of its key components was observed in the OMVs group compared with control group (P < 0.05). We identified the key differentially expressed gene B3GAT1 using high-throughput sequencing. Subsequent rescue experiments both in vitro and in vivo demonstrated that overexpression of B3GAT1 effectively restored glycocalyx integrity following injury (P < 0.05). Notably, Porphyromonas gingivalis peptidylarginine deiminase (PPAD) was found to promote endovascular glycocalyx injury by citrullinating histone H3, thereby decreasing the expression of B3GAT1 (P < 0.05).

Conclusions: Our experiments demonstrated that biomarkers of endothelial glycocalyx injury were significantly higher in patients with stage III-IV periodontitis and PPAD could enter the cell nucleus, playing a vital role in vascular endothelial glycocalyx injury through the CitH3/B3GAT1 pathway.

Subarachnoid hemorrhage (SAH) is a devastating stroke subtype often leading to poor neurological outcomes. Iron homeostasis imbalance is a key contributor to cognitive dysfunction in neurological diseases. Extracellular vesicles, including exosomes (EXs), are crucial mediators of intercellular communication. This study investigated the role of EXs in post-SAH iron metabolism and neurological impairment. We isolated EXs from various neural cells (microglia, astrocytes, endothelial cells, neurons; n = 4-6 independent isolations) in vitro after SAH mimicked by oxyhemoglobin (OxyHb) or hemin. We found that microglial EXs (MC-EXs) were significantly enriched in iron and potently impaired neuronal viability. Using specific inhibitors and fluorescence imaging, we demonstrated that neurons internalize MC-EXs primarily via dynamin-dependent, clathrin-, caveolae-, and lipid raft-mediated endocytosis. Combining transcriptomic analysis with in vivo and in vitro SAH models, we discovered that iron-overloaded MC-EXs induce neuronal ferroptosis. In mice, intranasal administration of MC-EXs (10⁹ particles/day for 3 days, n = 10/group) exacerbated SAH-induced motor, sensory, and cognitive deficits. Bioinformatic analysis and experimental validation (including C3 siRNA knockdown) identified the complement C3/C5/NF-κB pathway as a key molecular mechanism through which iron-overloaded MC-EXs trigger ferroptosis. This research provides evidence for a novel EX-mediated mechanism for iron toxicity in SAH, highlighting MC-EXs and the C3/C5/NF-κB axis as potential therapeutic targets.

Catalyzing the glucose cascade reaction to impair tumor cell energy metabolism represents a promising strategy for tumor therapy. However, the application of natural enzymes as therapeutic agents remains limited by various challenges. Although nanozymes with multi-enzyme activities, including glucose oxidase-like (GOx-like) activity, have been reported, their development often involves complex material combinations and cumbersome synthesis processes. Here, we develop a nanozyme with GOx-, peroxidase (POD)-, superoxide dismutase (SOD)-, and NADH oxidase (NOX)-mimic activities by simply controlling the AuPt alloy ratio. The optimal cascade activity was observed for the nanozyme at an Au: Pt proportion of 13:7. Density functional theory (DFT) calculations revealed that Au sites drive glucose dehydrogenation (GOx-like), while Pt sites facilitate hydroxyl radical (•OH) generation (POD-like). Both in vitro and in vivo data indicated that Au₁₃Pt₇ nanozymes disrupt tumor redox/metabolic homeostasis by depleting glucose and generating cytotoxic •OH, and impairing mitochondrial function via NOX-like, thereby inducing cell apoptosis. Notably, apoptotic immunogenic cell death (ICD) induces antitumor immunity and suppresses tumor metastasis. This study presents an innovative strategy for engineering nanozymes with multi-enzyme catalytic capabilities while demonstrating the promising application of alloy-based nanozymes in synergistic metabolic-immunotherapy.

Organ adhesions pose a significant clinical challenge, arising from factors such as congenital adhesions caused by embryonic developmental abnormalities, as well as acquired adhesions resulting from inflammation or surgery. This phenomenon commonly occurs in conditions such as peritonitis, pelvic inflammatory disease, and malignant tumor infiltration. Postoperative adhesions might cause serious complications such as chronic pain, infertility and intestinal obstruction. Traditional treatment methods (anti-adhesion membranes and drug therapy), have some limitations, including insufficient mechanical properties, poor biocompatibility or difficulty in achieving full intervention. As a novel generation of biomaterials, hydrogels demonstrate significant advantages in preventing and treating organ adhesions: physical barriers, biocompatibility, multidimensional functional integration, controlled drug release, dynamic adaptation to complex environments, and intelligent responsiveness. This review aims to systematically summarize research progress on hydrogels in organ adhesion prevention and treatment, integrating their mechanisms of action across different pathological stages, material innovations, and organ application cases. This study provides strategies to overcome clinical translation bottlenecks and outlines future research directions.

Proteolysis-targeting chimeras (PROTACs) represent a transformative therapeutic modality that leverages the endogenous ubiquitin-proteasome system (UPS) to achieve targeted protein degradation. These heterobifunctional molecules facilitate the recruitment of E3 ubiquitin ligases to a protein of interest (POI), promoting its ubiquitination and subsequent proteasomal degradation. In contrast to conventional inhibitory approaches, PROTACs operate catalytically, enabling the degradation of a wide spectrum of targets-including those harboring drug-resistant mutations-at significantly lower doses. These attributes have positioned PROTACs as promising agents, particularly in oncology, where their efficiency and broad applicability have been increasingly demonstrated. Nonetheless, clinical translation of PROTACs faces challenges such as poor bioavailability, insufficient tumor-specific accumulation, and off-target effects. The integration of nanomedicine-based delivery platforms offers a viable path to overcome these limitations by enhancing drug stability, improving tissue selectivity, and reducing systemic toxicity. This review outlines the rational design principles underlying nano-PROTACs, highlights recent advances in nanoformulations aimed at optimizing their delivery and efficacy, discusses emerging combination regimens and innovative design strategies, and critically assesses the translational challenges and future directions of nano-PROTACs. Overall, nano-PROTAC technology has pioneered a brand-new approach in the field of disease treatment, providing unprecedented opportunities for precision medicine and personalized disease treatment.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons. The development of effective neuroprotective therapies is severely hampered by the blood-brain barrier (BBB), which restricts drug delivery to the central nervous system. This study aimed to develop a novel brain-targeted nanodelivery system by functionalizing extracellular vesicles (EVs) with a rabies virus glycoprotein (RVG)-derived peptide to deliver echinatin (Echi), and to systematically evaluate its therapeutic efficacy and underlying mechanisms in a mouse model of PD.

Results: We successfully engineered the nanotherapeutics, termed RVG-EVs@Echi, which efficiently crossed the BBB and selectively accumulated in DA neurons and microglia following systemic administration. In a chronic MPTP-induced mouse model of PD, treatment with RVG-EVs@Echi significantly ameliorated motor deficits and rescued tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and striatum, with no detectable peripheral toxicity. Mechanistically, RVG-EVs@Echi exerted potent neuroprotective effects by upregulating insulin-like growth factor-2 (IGF-2) and activating the downstream PI3K/Akt/Nrf2 signaling cascade, which mitigated oxidative stress and neuronal apoptosis. Furthermore, integrated multi-omics analyses revealed that RVG-EVs@Echi treatment modulated metabolic profiles in the midbrain and gut, and partially restored MPTP-induced gut microbiota dysbiosis.

Conclusions: This study demonstrates that RVG-EVs@Echi represents a safe, noninvasive, and effective nanotherapeutic platform for targeted brain delivery in PD. By activating the IGF-2/PI3K/Akt/Nrf2 neuroprotective pathway and modulating the gut-brain metabolic axis, this targeted delivery system presents a highly promising and translatable strategy for the treatment of PD and other neurodegenerative diseases.

Fungal biofilms represent a major therapeutic hurdle due to their drug resistance and immune evasion. Here, we report a cocrystal-inspired nano-assembly strategy that co-assembles glycyrrhizic acid (GA), a natural triterpenoid saponin, with azole antifungal agents into multifunctional nanoparticles. The GA-azole co-assemblies, stabilized via hydrogen bonding and hydrophobic interactions, exhibit cocrystal-like properties while preserving the bioactivities of both components. This hybrid nanoplatform improves azole solubility and permeability and leverages GA's intrinsic membrane-disrupting, ROS-scavenging, and immunomodulatory effects. Mechanistic studies revealed that the nanoparticles effectively disrupted Candida albicans biofilms by impairing matrix structure and suppressing hyphal formation. Transcriptomic and qRT-PCR analyses demonstrated GA-azole co-assemblies downregulated genes involved in ergosterol biosynthesis, oxidative stress response, and morphogenesis. Additionally, GA-azole nanoparticles promoted macrophage polarization toward an anti-inflammatory M2 phenotype and alleviated oxidative stress, by activating the Nrf2/HO-1 antioxidant pathway, thereby modulating the excessive inflammation stimulated by fungal infection. In vitro and in vivo experiments, including a murine perianal infection model, showed significant reductions in fungal burden, biofilm thickness, and local inflammation without systemic toxicity. This work presents a multi-targeted nanotherapeutic strategy combining enhanced drug delivery, antifungal synergy, immune regulation to combat biofilm-associated fungal infections.