Journal of Nanobiotechnology最新文献

Background: Melanoma represents a highly aggressive and immunotherapy-resistant malignancy with limited immunotherapy efficacy, underscoring the urgent need for novel treatment strategies that integrate precise diagnosis and potent immunomodulation. The combination of photothermal therapy (PTT) and STING pathway activation has emerged as a promising approach to potentiate antitumor immunity. Nevertheless, it remains challenging to integrate real-time deep-tissue imaging with spatiotemporally synchronized immunostimulation within a single nanoplatform, especially for the effective treatment of advanced melanoma.

Results: Herein, we report a mitochondria-targeted nanotheranostic agent (IRM) constructed through molecular co-assembly of a STING agonist (MSA-2) and a lab-synthesized NIR-Ⅱ fluorophore (IR-817). This nanoplatform enables simultaneous NIR-Ⅱ fluorescence imaging and high-efficiency photothermal conversion (η = 52.79%). More importantly, it ensures efficient, on-demand drug action through spatiotemporally controlled delivery. Under 808 nm laser irradiation, IRM induced localized hyperthermia that provoked pyroptosis and immunogenic cell death (ICD) in primary melanoma tumors. Concurrently, the photothermal stimulus promoted the rapid release of MSA-2, which synergistically activated the STING pathway in dendritic cells (DCs). This event drove immunometabolic reprogramming of the tumor microenvironment, elicited a robust systemic cytotoxic T-cell response, and effectively reversed the immunosuppressive state. This cascade of biological events ultimately led to significant inhibition of distant tumors, demonstrating a robust abscopal effect. Crucially, this therapeutic effect was strictly STING-dependent: in STING-KO mouse models, the suppression of distant tumors was completely abolished following the same treatment. These complementary experimental outcomes directly confirm the indispensable synergy between PTT and STING pathway activation, which together constitute the core mechanism underlying the induction of systemic antitumor immunity by the IRM nanoplatform.

Conclusions: Our study illustrates that the IRM nanoplatform effectively merges multimodal imaging with immunometabolic modulation, establishing a durable and systemic antitumor immunity. This work offers a translatable strategy for combinational photo-immunotherapy against advanced melanoma.

Intervertebral disc degeneration (IVDD) is the primary cause of chronic low back pain, with the senescence of nucleus pulposus cells (NPCs) as its core driving mechanism. Mitochondrial homeostasis acts as a critical mediator linking cellular stress responses to the senescence program of nucleus pulposus cells. Recent studies have indicated that the transplantation of apoptotic extracellular vesicles (ApoEVs) derived from the apoptotic mesenchymal stem cells (MSCs) represents a novel direction for tissue regeneration therapy. Given that the pathological microenvironment of IVDD exhibits hypoxic-inflammatory characteristics, the functional regulatory effects of ApoEVs pretreated under such conditions remain unclear. Here, we aimed to assess whether modulation of the MSCs culture microenvironment (hypoxia alone versus hypoxic-inflammatory conditions) generates ApoEVs (specifically I-ApoEVs) with enhanced therapeutic efficacy in the context of IVDD repair. A secondary focus of this study was to clarify the underlying mechanism through which such therapeutic effects are mediated by the regulation of mitochondrial homeostasis. Notably, the results demonstrated that I-ApoEVs were significantly superior to enhance the viability of NPCs and improve mitochondrial function. These findings suggest that the combined hypoxic-inflammatory pretreatment can more efficiently enhance the capacity of MSCs-derived ApoEVs to regulate mitochondrial homeostasis, thereby providing experimental evidence for optimizing ApoEV-based therapeutic strategies for IVDD.

Background: Inflammatory arthritis (IA) is a group of chronic progressive inflammatory diseases characterized by the destruction of joints. The clinical efficacy and safety of the current drugs for patients with IA still need improvement, suggesting the importance of developing new therapeutic agents with the potential to specifically target inflammatory sites and precisely intervene in pathogenic molecules.

Results: Previously, we demonstrated that elevated PIM1 expression in CD4⁺ T cells could serve as a therapeutic target for IA. Herein, we constructed the neutrophil membrane-coated and MMP2-cleaved peptide-linked nanoparticles (NM@MRP-NP) to specifically deliver PIM1 inhibitor to CD4⁺ T cells in inflamed joints. In vitro experiments showed that NM@MRP-NP was a structurally defined, biologically stable nanotherapeutic system with efficient drug loading, which could be successfully deliver AZD1208, the PIM1 inhibitor, to activated CD4⁺ T cells upon exposure to MMP2. Besides, NM@MRP-NP effectively inhibited the differentiation of Th17 cell and suppressed the secretion of Th17-associated pathogenic cytokines in the presence of MMP2. In terms of mechanism, NM@MRP-NP regulates mitochondrial enzyme activity, including PDH, KGDH, and ATPase, through mito-Ca²⁺ influx, therefore accelerating OXPHOS to promote Th17 cell differentiation. In vivo assays determined that NM@MRP-NP specifically targeted the inflammatory joints of the SKG mice, a murine model of IA featuring disordered T cells, and then exhibited outstanding therapeutic effects on SKG mice through suppressing Th17 cells response under the condition of ensuring safety.

Conclusion: These results suggested that NM@MRP-NP was a structurally defined, biologically stable, inflammatory-targeted and conditionally releasing nanotherapeutic system with efficient drug delivery, which could provide new insight into the targeted interventions for IA.

Myocardial infarction (MI) is a complex pathological process characterized by vascular injury, myocardial necrosis, and dynamic immune interactions. Migrasomes are recently identified organelles generated during cell migration, serving as key mediators of intercellular communication. However, the contribution of migrasomes to immune-mediated myocardial injury remains largely unexplored. This study demonstrated an increase in migrasome production following MI. Migrasomes can be produced by macrophages, and M1 macrophage-derived migrasomes (M1-Migs) were particularly found to exacerbate myocardial tissue injury. Quantitative proteomic sequencing demonstrated increased levels of guanylate binding protein 5 (GBP5) within M1-Migs. Viral knockdown experiments demonstrated that M1-Migs mediate their deleterious effects predominantly via GBP5. Pathway enrichment analysis further indicated that GBP5 activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, thereby promoting myocardial cell apoptosis. Analysis of clinical samples has also demonstrated a positive correlation between macrophage-derived migrasomes and MI. Notably, colchicine may mitigate post-infarction myocardial injury by suppressing migrasome production by M1 macrophages. Overall, these findings identify macrophage-derived migrasomes as key amplifiers of myocardial injury, providing potential therapeutic targets for MI and may provide additional evidence for the clinical application of colchicine.

Lung cancer (LC) remains a leading cause of cancer-related mortality worldwide, and the limited efficacy of immunotherapy due to treatment resistance underscores the urgent need for new therapeutic strategies. In the present study, CD93-targeted poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating resveratrol (CD93-NPs@RSV) were developed to remodel the metabolic fitness of CD8⁺ tumor-infiltrating lymphocytes. The nanoparticles were precisely engineered and characterized using dynamic light scattering, transmission electron microscopy, and in vivo imaging, which confirmed their stability and tumor-targeting capability. Mechanistic studies revealed that CD93-NPs@RSV suppressed CD93 expression, facilitated apoptosis-inducing factor (AIF) mitochondrial translocation, and activated oxidative phosphorylation (OXPHOS), thereby enhancing T cell function in the tumor microenvironment. Transcriptomic and proteomic analyses further confirmed regulation of the CD93-AKT-PAK5-AIF signaling axis. In a Lewis LC model, CD93-NPs@RSV significantly inhibited tumor progression and displayed strong synergy with anti-PD-1 therapy, resulting in improved survival outcomes. Collectively, our study demonstrates that CD93-NPs@RSV provide a powerful nanotechnology-driven approach to reverse immunotherapy resistance by reprogramming T cell metabolism. These findings establish a promising paradigm for precision cancer immunotherapy and underscore the translational potential of targeted nanomedicine in overcoming therapeutic bottlenecks in LC.

Type 1 Diabetes Mellitus (T1DM) is a chronic autoimmune disease characterized by the destruction of pancreatic β-cells. Growing evidence indicates that immune dysregulation along the gut-lung axis contributes to its pathogenesis. This study aimed to develop a selenium-loaded sustained-release Schizophyllan (Se/s-SPG) composite and investigate its mechanism of action in alleviating T1DM-associated inflammatory immune responses through modulation of the gut microbiota and the Toll-like receptor 4 (TLR4)/Nuclear Factor kappa B (NF-κB) signaling pathway. A T1DM model was established using non-obese diabetic (NOD)/LtJ mice. Comprehensive analyses were performed, including 16 S rRNA sequencing, RNA sequencing (RNA-seq), Western blot (WB), Enzyme-linked immunosorbent assay (ELISA), and Flow Cytometry to assess the effects of Se/s-SPG on gut microbial diversity, pancreatic structure and function, immune cell subset distribution, and inflammatory signaling pathways. The results demonstrated that Se/s-SPG significantly improved glucose metabolism, restored intestinal and pulmonary barrier integrity, and regulated T cell subset differentiation as well as macrophage polarization. This study proposes a novel intervention strategy targeting the gut-lung axis for T1DM and highlights its potential for clinical translation.

Background: Traumatic optic neuropathy (TON) is a devastating cause of irreversible vision loss for which no effective treatment currently exists. Its poor prognosis stems from two major challenges: the limited regenerative capacity of retinal ganglion cells (RGCs) and the hostile, inflammation-driven environment that follows injury.

Results: In this work, using transcriptomic bioinformatic and histopathological analysis, we discovered that mechanical trauma and subsequent neuroinflammation trigger microglial pyroptosis through the NLRP3/CASP1/GSDMD pathway. This process amplifies inflammatory cascades and exacerbates RGC degeneration via microglia-neuron interactions. To overcome these dual barriers, we engineered a microglia-targeted lipid nanoparticle (LNP) platform co-delivering disulfiram (DSF), a selective GSDMD inhibitor, together with self-amplifying mRNA (saRNA) encoding ciliary neurotrophic factor (CNTF). We found that this combinatorial strategy concurrently suppresses pyroptosis-driven neuroinflammation while providing sustained neurotrophic support. Through comprehensive in vitro and in vivo evaluations, the co-delivery system showed enhanced RGC survival, remarkable axonal regeneration, and eventually significant restoration of visual function.

Conclusions: In summary, our results demonstrate that a coordinated strategy targeting both neuroinflammatory mechanisms and regenerative pathways yields superior therapeutic outcomes in TON. This work underscores the potential of integrated RNA-small molecule therapies as a promising multi-target treatment paradigm, with broad applicability for other neuroinflammatory and neurodegenerative diseases.

Chronic refractory wounds, such as diabetic foot ulcers, present significant clinical challenges due to a dysregulated healing microenvironment. Extracellular vesicles (EVs) have emerged as promising therapeutic agents owing to their pro-angiogenic, anti-inflammatory, and regenerative properties. However, their clinical translation is hampered by rapid clearance and instability at the wound site. Hydrogel-based delivery systems offer an effective strategy to overcome these limitations by providing a protective and tunable platform for sustained EVs release. This review systematically synthesizes contemporary advances in EVs hydrogel (EVH) systems for chronic wound therapy. We critically evaluate design strategies encompassing various hydrogel matrices (natural, synthetic, and smart responsive), engineering approaches for EVs modification, and controlled-release mechanisms that collectively enhance therapeutic efficacy. By integrating findings from preclinical studies across diverse wound models, we highlight the synergistic roles of EVH systems in promoting angiogenesis, modulating immune responses, and accelerating tissue regeneration. Furthermore, this review addresses key translational challenges, including scalable EVs production, standardization, biosafety, and regulatory pathways. Finally, we provide forward-looking perspectives on the clinical translation of next-generation, intelligent EVH systems, aiming to bridge the gap between innovative design and practical therapeutic application.

Multiple outbreaks of Ebola virus in West Africa have posed significant threats to global public health owing to its high pathogenicity and fatality rates. Current treatments for Ebola Virus Disease are limited, underscoring the imperative for novel antiviral therapies. VP30, a critical RNA synthesis factor, interacts with nucleoprotein (NP) to facilitate Ebola viral genome transcription and replication. Notably, the host ubiquitin-ligase retinoblastoma-binding protein 6 (RBBP6) binds to VP30 at the same interface as NP, thereby inhibiting VP30-NP interactions and indicating that targeting this interface could advance antiviral drug development. In this study, we engineered six peptide mutants through amino acid substitutions at key VP30 binding sites. These mutants were fused to DNA-binding protein from starved cells 4 (DPS4) to assemble nanoparticles, enabling surface display of the peptides. Antiviral effects were evaluated using minigenome and transcription and replication-competent virus-like particles (trVLPs) systems. Among the variants, RPL1 and NPL3 peptides exhibited relatively strong apparent affinities with the VP30 and potent antiviral activity by disrupting Ebola viral genome transcription and replication. To elucidate the binding details between the peptides and VP30, we determined crystal structures of complexes between RPL1 or NPL3 peptides and VP30 via X-ray crystallography. Concurrently, molecular dynamics (MD) simulations revealed the dynamic binding processes of these peptides to VP30. Structural analyses confirmed that the peptides bind to the VP30/NP interface and compete with NP. Our findings demonstrate that DPS4-fusion peptides effectively deliver peptides into cells as nanoparticles and inhibit VP30-NP interactions, presenting a novel antiviral strategy for Ebola virus.