Theranostics最新文献

Rationale: Nuclear factor erythroid 2-like 1 (Nrf1/NFE2L1) is a crucial redox-sensitive factor essential for mitochondrial homeostasis. However, its function in controlling macrophage-associated liver inflammation and fibrosis remains to be fully understood. Herein, this study was conducted to elucidate the roles of macrophage Nrf1 in regulating liver fibrosis. Methods: Expression levels were analyzed in human liver tissues collected from individuals diagnosed with or without liver fibrosis. High-fat diet feeding, carbon tetrachloride injection or bile duct ligation was performed respectively to established three mouse models of liver fibrosis. Myeloid-specific Nrf1-knockout (Nrf1^M-KO ) mice were developed to investigate the role and underlying mechanisms of macrophage Nrf1 in vivo and in vitro. Results: Macrophage Nrf1 expression was markedly reduced in liver samples from both humans and mice with liver fibrosis. The deletion of myeloid Nrf1 remarkably accelerated liver inflammation and fibrosis. Macrophages from Nrf1^M-KO mice exhibited enhanced M1 polarization and mitochondrial dysfunction. Mechanistically, Nrf1 directly binds to Foxo1 and inhibits its transcriptional activity. The target gene KLF16, regulated by the Nrf1-Foxo1 complex, is crucial for modulating mitochondrial function and immune response. Conclusions: Our study highlights the functional properties of macrophage Nrf1-Foxo1 axis in controlling mitochondrial reprogramming and liver fibrosis progression.

Rationale: High-intensity psychological and physiological stress contributed greatly to development of cardiac disorders in contemporary society. However, the underlying molecular mechanisms remain largely unknown. Synaptotagmin-7 (Syt7), a Ca²⁺ sensor with high affinity, has been associated with synaptic transmission and tumor progression, but its role in cardiac stress responses remains poorly defined. Methods: Corticosterone (CORT) was used to induce stress injury in vivo and in vitro. The expression of Syt7 was modulated by genetic knockout, injection of adenoviral siRNA or injection of adeno-associated virus serotype 9 (AAV9) shRNA. Cardiac function and remodeling were evaluated by echocardiography, electrocardiography, and histological staining. Necroptosis was analyzed by propidium iodide (PI) staining, lactate dehydrogenase (LDH) release detection, and necroptosis marker levels. Ca²⁺ overload, ROS production, mitochondrial permeability transition pore (mPTP) opening, and bioenergetic profiling were assessed to evaluate mitochondrial function. Co-IP assay was performed to detect protein interaction, and ChIP- qPCR was performed to assess transcriptional regulation. Results: Syt7 expression was significantly upregulated in both cardiomyocytes and heart tissues exposed to CORT. Both genetic knockout and cardiomyocyte-specific knockdown of Syt7 significantly preserved cardiac function and rhythm, and alleviated myocardial hypertrophy and fibrosis in CORT-treated mice. Mechanistically, Syt7 regulated necroptosis by promoting calcium overload, ROS production, mitochondrial ΔΨm dissipation, and mPTP prolonged opening. Notably, Syt7 interacted with transcription factor p53 and enhanced p53- mediated transcription of Bcl-2 homologous antagonist/killer (Bak). Syt7, p53 and Bak constitute a novel signaling axis to regulate mitochondrial dysfunction and necroptosis. Therapeutically, cardiac delivery of Syt7-targeting siRNA via adenoviral vectors significantly alleviated structural remodeling, electrophysiological instability, and myocardial necrosis in CORT-challenged mice. Conclusions: The study identified Syt7 as a novel upstream regulator involved in cardiomyocyte necroptosis triggered by stress stimuli through a p53-Bak-mPTP pathway. Therapeutic targeting of Syt7 offers a promising strategy for protecting the heart against psychological or neuroendocrine stress-related injury.

Background: Regulating the morphology structure of sonosensitizers and nanozymes is crucial to improve sonodynamic and enzyme-mimic activities. Methods: We report for the first time the utilization of Cu₂O nanospheres as the sacrificial templates for the synthesis of hollow RuO₂ nanospheres (H-RuO₂) for high-efficiency sonodynamic and chemodynamic therapy (SDT/CDT). We then utilized NIR phosphorescence carbon dots (CDs) as the auxiliary sonosensitizers to sensitize H-RuO₂ for the construction of CD@H-RuO₂ heterojunctions. Results: Compared with solid nanoparticles, nanosheets, and other structures, the hollow RuO₂ (H-RuO₂) nanostructures are expected to exhibit stronger catalytic activity due to their larger specific surface area and more catalytic active sites. The improved electron-hole separation kinetics enable CD@H-RuO₂ nanozymes with significantly enhanced sonodynamic and multienzyme-mimic activities. CD@H-RuO₂-triggered cascade amplification of antitumor immune response was realized by the heterojunction construction, GSH depletion, and relief of hypoxia co-augmented ROS yield, which significantly induced a robust ICD. Conclusion: CD@H-RuO₂-mediated SDT and CDT co-amplified immunotherapy have shown significant antitumor effects, resulting in the eradication of primary tumors and the inhibition of distant tumor growth. This study offers hopeful insights into the fabrication of heterojunctions for sonodynamic/chemodynamic-activated immunotherapy.

Background: Although autologous whole tumour cells provide broad-spectrum antigens for personalised cancer vaccines, their weak immunogenicity necessitates adjuvant co-delivery systems. Methods: We developed a conjugate adjuvant (G-PL) by coupling modified yeast β-glucan with poly-D-lysine. Electron microscopy confirmed its binding to GL261 cell membranes. The adjuvant-cell complex (ICC@G-PL) was constructed by coating irradiated tumour cells with G-PL. We evaluated the recruitment/activation of dendritic cells (DCs), lymph node priming, tumour-specific immunity, and therapeutic efficacy in glioblastoma, colon cancer, and melanoma models. Dectin-1-mediated Th17 induction was analysed via Western blotting and flow cytometry. Results: G-PL (≤ 500 μg/mL) rapidly adhered to cell membranes without cytotoxicity. In vitro, it enhanced DC uptake of tumour components, maturation, and non-pathogenic Th17 differentiation. In vivo, ICC@G-PL recruited DCs at injection sites, activated draining lymph nodes, and elevated plasma levels of IL-12, TNF-α, and IFN-γ. The vaccine prolonged survival in both therapeutic and preventive models, increasing intratumoral CD8⁺/CD4⁺ T cell ratios, M1 macrophages, and neutrophils. Dectin-1 downregulation in DCs correlated with Th17-driven anti-tumour responses. Conclusions: G-PL, a novel β-glucan-based adjuvant, enables rapid construction of autologous whole-cell vaccines. This strategy enhances tumour-specific immunity and reprogrammes the tumour microenvironment, offering a universal platform for personalised cancer immunotherapy.

Rationale: Ferroptosis-induced tumor cell death and immune activation represent promising strategies for overcoming therapeutic resistance in triple-negative breast cancer (TNBC). However, clinical application remains limited by poor oral absorption, transient immune activation, and systemic toxicity. Methods: We developed an orally administrable nanoplatform (MCT-NE#9) co-delivering docetaxel (DTX) and atorvastatin (ATV), designed to enhance intestinal uptake via bile acid and vitamin transporters. Pharmacokinetic, in vitro, and in vivo studies were conducted to evaluate drug absorption, sustained ferroptosis, and immune modulation. Results: MCT-NE#9 markedly improved oral bioavailability (659% for ATV, 851% for DTX) and sustained intratumoral drug levels under a low-dose metronomic regimen. Mechanistically, it induced sustained ferroptosis by promoting iron accumulation, lipid peroxidation, and GPX4 suppression, while remodeling the tumor immune microenvironment. Treatment increased M1 macrophages and antigen-presenting cells and reduced TGFβ1, regulatory T cells, and M2 macrophages. In vivo, oral MCT-NE#9 suppressed tumor growth by 50.4%, with enhanced efficacy (70.3% inhibition) when combined with anti-CD47 therapy. Conclusion: MCT-NE#9 enables a synergistic, low-toxicity chemo-immunotherapeutic strategy by sustaining ferroptosis and reprogramming the immune microenvironment via transporter-targeted oral delivery. This ligand-directed nanoplatform offers a clinically translatable approach for effective TNBC treatment.

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy with limited disease-specific imaging options. Current diagnostic methods often fail to detect early disease states and minimal residual disease, highlighting the need for more precise molecular imaging and targeted therapeutic approaches. We developed a radiolabeled nanobody targeting B-cell maturation antigen (BCMA) to enable both high-contrast molecular imaging and targeted radioligand therapy in human MM models. Methods: A high-affinity anti-BCMA nanobody was labeled with [¹⁸F]FPy-pyridine prosthetic group for PET imaging and [¹³¹I]I for radioligand therapy. Target expression and in vitro binding affinity and specificity were assessed using biolayer interferometry, flow cytometry, and cell-based assays. PET imaging studies were performed in subcutaneous MC38-human BCMA xenografts and systemic human MM models (H929 and RPMI8226 cell lines) administered intravenously in NSG mice. Therapeutic efficacy was evaluated using a fractionated treatment regimen with [¹³¹I]I-BCMA-Nb (four weekly injections of 7.4 or 18.5 MBq), monitoring tumor burden via bioluminescence imaging and [¹⁸F]FDG-PET. Toxicity assessment included body weight monitoring, complete blood counts, biochemical analyses, and histopathological examination. Results: [¹⁸F]FPy-BCMA-Nb demonstrated high binding affinity and excellent tumor specificity with rapid systemic clearance. PET imaging showed significantly higher uptake in BCMA-positive lesions (6-8% ID/g) compared to controls (1% ID/g), with minimal kidney retention (<1% ID/g by 3 h). In systemic MM models, the tracer specifically targeted bone marrow lesions with high tumor-to-background ratios. Therapeutic studies revealed dose-dependent tumor regression, with the 18.5 MBq [¹³¹I]I-BCMA-Nb regimen achieving 100% complete remission in treated mice. Biochemical and histopathological analyses confirmed minimal systemic toxicity, restoration of normal hematopoiesis, and significant reduction in BCMA expression and proliferation markers post-treatment. Conclusion: This BCMA-targeted nanobody platform offers a promising theranostic approach for precise detection and treatment of disseminated multiple myeloma. The combination of exceptional tumor specificity, minimal off-target accumulation, rapid clearance, and potent therapeutic efficacy, along with a favorable safety profile, supports its potential for clinical translation in MM diagnosis and therapy.

Rationale: Delayed fracture healing often results from impaired osteocyte network reconstruction and inadequate vascularization. Our prior work demonstrated that osteocytes engineered to overexpress Dll4 (Dll4-osteocytes) exert dual pro-osteogenic/angiogenic effects. Thus, this study explores the exosomes derived from Dll4-osteocytes (Dll4-Exo) as a cell-free strategy to coordinate bone-vascular regeneration and accelerate repair. Methods: Dll4-Exo were isolated from lentivirus-transduced Dll4-osteocytes. Mouse bone marrow stromal cells (ST2 cells) and human umbilical vein endothelial cells (HUVECs) were treated with Dll4-Exo to evaluate osteogenesis (ALP staining, mineralization, qRT-PCR) and angiogenesis (scratch/transwell migration, tube formation). Notch dependence was tested with γ-secretase inhibitor DAPT. In vivo, Dll4-Exo was locally administered in a mouse tibial fracture model. Healing was assessed via X-ray imaging, histology, immunohistochemistry, and immunofluorescence staining at days 14, 21, and 28. Exosomal miRNA profiles were analyzed by sequencing, and miR-23a-5p function was validated through mimic/inhibitor transfections. Results: Dll4-Exo activated Notch signaling in ST2 cells, significantly upregulating osteogenic genes (Alpl: 9.4-fold increase; mineralization: 62% increase) and enhancing HUVEC migration (2.6-fold) and tube formation. In the fracture model, Dll4-Exo accelerated callus formation, improved bone remodeling (OCN: 1.52-fold increase), and promoted revascularization (CD31⁺ vessel density: 1.56-fold increase with enhanced maturity). Through miRNA sequencing, miR-23a-5p was identified as the most enriched miRNA in Dll4-Exo, which was functionally transferred to both ST2 cells (3.0-fold increase) and HUVECs (2.7-fold increase). Mechanistic studies demonstrated that the pro-osteogenic effect of Dll4-Exo is exerted by miR-23a-5p via Notch signaling activation in ST2 cells, whereas its pro-angiogenic effect on HUVECs occurs through miR-23a-5p-independent mechanisms. Conclusion: Dll4-Exo carrying miR-23a-5p activates Notch-dependent osteogenesis in ST2 cells, while stimulating angiogenesis in HUVECs through alternative mechanisms, synergistically accelerating fracture healing and osteocyte network reconstruction. This engineered exosome platform represents a clinically viable strategy for bone regeneration.

Rationale: Synthetic molecules, meticulously designed according to the "sticker-and-spacer model", tend to form coacervates via liquid-liquid phase separation (LLPS), thereby acquiring properties beyond their discrete and soluble states. However, natural compounds, such as those from traditional Chinese medicines (TCMs), are not known to undergo phase separation. In this study, we demonstrate that curcumin, the active ingredient in the spice turmeric, forms phase-separated fluorescent coacervates when diluted from a concentrated organic-solvent solution into an aqueous solution. Methods: Curcumin coacervates were formed by diluting a concentrated stock solution in organic solvents into the aqueous solution. We utilized the coacervate droplets to encapsulate and transport various biomacromolecules, such as proteins and nucleic acids, across the plasma membrane into the cell. Supramolecular interaction between β-cyclodextrin (β-CD) and curcumin disassembles curcumin coacervates, leading to cargo release in the cytosol. Results: Intravenously injected curcumin coacervates spontaneously enrich in the tumor tissue in tumor-bearing BALB/c mice. Subsequent intratumoral injection of β-CD significantly enhances anticancer effects in mice, demonstrating the efficacy of coacervate-mediated siRNA drug delivery and supramolecular-interaction-responsive intracellular release in vivo. Conclusions: Taken together, we report here the coacervate-forming properties of the natural TCM compound curcumin, presenting a unique strategy for controlling coacervate states through supramolecular interactions with β-cyclodextrin in vitro and in vivo, along with the unexplored potential of curcumin coacervate-mediated siRNA delivery to enhance pyroptosis.

Renal diseases remain a major global health burden, with an estimated 850 million individuals affected by chronic kidney disease, acute kidney injury, glomerulonephritis, and diabetic nephropathy. These multifactorial diseases collectively account for substantial morbidity and mortality burdens. This grim trajectory demands urgent development of drugs that are capable of simultaneously enhancing renal efficacy while circumventing systemic toxicity. In response to this challenge, engineered nanoplatforms designed specifically for the treatment of kidney diseases have emerged as a promising solution. These nanoplatforms offer the unique ability to deliver targeted therapeutics directly to specific regions of the kidney, thereby improving drug efficacy while reducing off-target effects. Unlike the well-established oncological applications of nanomedicine, renal-specific formulations remain in their developmental nascency. Nevertheless, accumulating preclinical evidence indicates that nanotherapeutics hold significant promise for improving the clinical management of kidney diseases through targeted and mechanism-based interventions. The nephrotropic mechanisms and structural determinants of renal nanoplatforms fundamentally diverge from those of conventional nanotherapeutics. Therefore, a thorough understanding of the principles governing renal targeting is essential for designing nanomedicines that achieve precise kidney-specific delivery while ensuring biosafety. In this review, we summarize the current understanding of structure-function relationships that govern the targeting efficiency and biodistribution of nanoparticles in the kidney, with a focus on passive targeting mechanisms driven by key physicochemical parameters, such as particle size, surface charge, shape, and density, as well as active targeting strategies based on specific receptor-ligand interactions.

Chronic wounds associated with diabetes present considerable clinical hurdles, primarily due to delayed tissue repair and dysregulated immune activity. The imbalance in immune responses, including impaired macrophage polarization, excessive neutrophil activation, and oxidative stress, further hampers the healing process. The application of immunomodulatory biologics as a novel treatment method for diabetic wounds often yields limited results due to rapid degradation and lack of targeting. Hydrogels not only prevent rapid drug degradation but also allow for conditional responsiveness and targeted delivery. Therefore, hydrogels loaded with immunomodulatory biologics emerge as a promising strategy, offering the capacity to reshape the immune milieu and promote regenerative outcomes. This review first outlines the role of immune system during the healing processes in normal and diabetic wounds. It then discusses the latest advancements in hydrogel delivery systems as part of immune-modulatory interventions, wherein hydrogels serve as pivotal carriers for (i) cell delivery, such as stem cells and macrophages; (ii) extracellular vesicles derived from both cellular and tissue sources, as well as extracellular vesicle mimetics; and (iii) bioactive substances, including oxygen-releasing microspheres, nanomaterials, and cytokines. Finally, this review focuses on the limitations of modulating immune responses in diabetic wound healing and proposes potential future directions.