Theranostics最新文献

Rationale: Postinterventional restenosis is a major challenge in the treatment of peripheral vascular disease. Current anti-restenosis drugs inhibit neointima hyperplasia but simultaneously impair endothelial repair due to indiscrminative cytotoxity. Stem cell-derived exosomes provide multifaceted therapeutic effects by delivering functional miRNAs to endothelial cells, macrophages, and vascular smooth muscle cells (VSMCs). However, their clinical application is severly limited by poor targeting and low tissue uptake in injured vessel. Methods: To address this challenge, we constructed platelet-mimetic exosomes (PM-EXOs) by fusing mesenchymal stem cell (MSC)-derived exosomes with platelet membrane in order to harness the natural ability of platelets to target vascular injury, evade clearance by the mononuclear phagocyte system, and penetrate into the intima by hitchhiking on inflammatory monocytes. Results: PM-EXOs demonstrated enhanced cellular uptake by endothelial cells and macrophages, exerting proangiogenic and immunomodulatory effects via the delivery of functional miRNAs in vitro. The intravenously administrated PM-EXOs exhibited extended circulation time and a 4-fold enhancement in targeting injured arteries compared to unmodified exosomes. In mouse and rat carotid artery injury models, PM-EXOs were shown to promote endothelial repair on the denuded arterial wall, lower the M1/M2 ratio of infiltrated macrophages, and eventually inhibit phenotypic switch of vascular smooth muscle cells and reduce the formation of neointima without causing systemic toxicity. Conclusions: This biomimetic strategy may be leveraged to boost the therapeutic index of exosomes and realize the multifaceted treatment of arterial restenosis.

Infectious bone defects present a significant clinical challenge, characterized by infection, inflammation, and subsequent bone tissue destruction. Traditional treatments, including antibiotic therapy, surgical debridement, and bone grafting, often fail to address these defects effectively. However, recent advancements in biomaterials research have introduced innovative solutions for managing infectious bone defects. GelMA, a three-dimensional network of hydrophilic polymers that can absorb and retain substantial amounts of water, has attracted considerable attention in the fields of materials science and biomedical engineering. Its distinctive properties, such as biocompatibility, responsiveness to stimuli, and customisable mechanical characteristics make GelMA an exemplary scaffold material for bone tissue engineering. This review aims to thoroughly explore the current literature on antibacterial and osteogenic strategies using GelMA hydrogels for the restoration of infected bones. It discusses their fabrication methods, biocompatibility, antibacterial effectiveness, and bioactivity. We conclude by discussing the existing challenges and future research directions in this field, with the hope of inspiring further innovations in the synthesis, modification, and application of GelMA-based hydrogels for infection control and bone tissue regeneration.

Reproductive health-related diseases have a significant impact on the well-being of millions of women worldwide, severely compromising their quality of life. Women encounter unique challenges in terms of reproductive health, including gynecological diseases and malignant neoplasms prior to pregnancy, as well as complications during pregnancy that greatly undermine their physical and mental health. Despite recent advancements in the field of female reproduction, substantial challenges still persist. To address these challenges, nanotechnology-based diagnostic and therapeutic strategies have emerged to provide intelligent detection and treatment for pathologies related to women's reproductive health. Although some progress has been made with nanotherapeutics in this domain, its application is still nascent due to the delicate and intricate nature of the female reproductive system. This review comprehensively presents the latest advancements in nanomedicine for regulating woman's reproductive health. Firstly, based on the time period of onset, nanomedicine applications are categorized into four subcategories: 1) preconception diseases such as polycystic ovary syndrome, endometriosis, and gynecologic malignancy treatment; 2) pregastrulation period diseases including placenta accreta spectrum disorders and ectopic pregnancy; 3) mid-term pregnancy diseases like preeclampsia; and 4) late pregnancy diseases such as deep vein thrombosis during pregnancy. The systematic introduction covers the progress made by nanomedicine in various disease areas. Finally, this article discusses the challenges faced by these nanomedicines from research to clinical translation while also highlighting future directions.

Background: Radiotherapy is a widely employed technique for eradication of tumor using high-energy beams, and has been applied to approximately 50% of all solid tumor patients. However, its non-specific, cell-killing property leads to inevitable damage to surrounding normal tissues. Recent findings suggest that radiotherapy-induced tissue damage contributes to the formation of a pro-tumorigenic microenvironment. Methods: Here, we utilized two mouse strains and two organ-targeted radiotherapy models to uncover the mechanisms underlying the development of the radiotherapy-induced microenvironment. Results: Radiotherapy-induced tissue damage stimulates infiltration of monocyte-derived macrophages and their differentiation into M2 macrophages, ultimately leading to fibrosis and the formation of a pro-tumorigenic microenvironment. Notably, SRC family kinases (SFKs) emerged as crucial factors in the formation of the radiotherapy-induced pro-tumorigenic microenvironment. SFKs activation in epithelial cells and fibroblasts was triggered by direct exposure to irradiation or M2 macrophage cytokines. Remarkably, the administration of SFK-targeted inhibitors reversed myofibroblast activation, effectively ameliorating fibrosis and the pro-tumorigenic microenvironment in radiated tissues. Further, combined administration of radiotherapy and SFK-targeted inhibitors significantly enhanced the survival of tumor-bearing mice. Conclusions: Reshaping the tissue microenvironment by targeting SFKs is a potential strategy for preventing metastasis and recurrence following radiotherapy. The finding that clinically imperceptible damage can trigger a pro-tumorigenic microenvironment suggests the need for combining SFK-targeted inhibitors with radiotherapy.

Rationale: The tertiary structure of normal podocytes prevents protein from leaking into the urine. However, observing the complexity of podocytes is challenging because of the scale differences in their three-dimensional structure and the close proximity between neighboring cells in space. In this study, we explored podocyte-secreted angiopoietin-like 4 (ANGPTL4) as a potential morphological marker via super-resolution microscopy (SRM). Methods and Results: Specimens from patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN), along with normal controls, were analyzed via immunofluorescence and immunohistochemistry to determine the expression and localization of ANGPTL4, confirming its extensive presence in podocytes across both healthy and diseased conditions. Immunoelectron microscopy revealed that ANGPTL4 is distributed throughout the podocyte cell body, primary processes, and foot processes. Compared with conventional podocyte markers such as nephrin and synaptopodin, ANGPTL4 excels in depicting the three-dimensional structure of podocytes via SRM imaging. We then refined a protocol using tyramide signal amplification staining and confocal microscopy to uniformly enhance podocyte fluorescence, facilitating the clinical assessment of biopsies. In patients diagnosed with MCD and FSGS, measurements of slit diaphragm density, primary process width, and foot process width were taken after further co-staining with nephrin to identify patterns of podocyte morphological alterations. Distinctive patterns of foot process effacement were identified in MCD and FSGS patients, with FSGS patients showing more pronounced podocyte injury. Conclusions: ANGPTL4 serves as a reliable morphological marker for podocyte analysis, offering enhanced visualization of their three-dimensional structure and facilitating the identification of distinct pathological changes in nephrotic syndrome patients.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults, characterized by resistance to conventional therapies and poor survival. Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has recently emerged as a promising therapeutic target for GBM treatment. However, there are currently no non-invasive imaging techniques to monitor the engagement of pro-ferroptotic compounds with their respective targets, or to monitor the efficacy of ferroptosis-based therapies. System xc-, an important player in cellular redox homeostasis, plays a critical role in ferroptosis by mediating the exchange of cystine for glutamate, thus regulating the availability of cysteine, a crucial precursor for glutathione synthesis, and influencing the cellular antioxidant defense system. We have recently reported the development and validation of [¹⁸F]hGTS13, a radiopharmaceutical specific for system xc-. Methods: In the current work, we characterized the sensitivity of various cell lines to pro-ferroptotic compounds and evaluated the ability of [¹⁸F]hGTS13 to distinguish between sensitive and resistant cell lines and monitor changes in response to ferroptosis-inducing investigational compounds. We then associated changes in [¹⁸F]hGTS13 uptake with cellular glutathione content. Furthermore, we evaluated [¹⁸F]hGTS13 uptake in a rat model of glioma, both before and after treatment with imidazole ketone erastin (IKE), a pro-ferroptotic inhibitor of system xc- activity. Results: Treatment with erastin2, a system xc- inhibitor, significantly decreased [¹⁸F]hGTS13 uptake and cellular glutathione content in vitro. Dynamic PET/CT imaging of C6 glioma-bearing rats with [¹⁸F]hGTS13 revealed high and sustained uptake within the intracranial glioma and this uptake was decreased upon pre-treatment with IKE. Conclusion: In summary, [¹⁸F]hGTS13 represents a promising tool to distinguish cell types that demonstrate sensitivity or resistance to ferroptosis-inducing therapies that target system xc-, and monitor the engagement of these drugs.

Recent innovations in medical imaging technology have placed molecular imaging techniques at the forefront of diagnostic advancements. The current research trajectory in this field aims to integrate personalized molecular data of patients and diseases with traditional anatomical imaging data, enabling more precise, non-invasive, or minimally invasive diagnostic options for clinical medicine. This article provides an in-depth exploration of the basic principles and system components of optical molecular imaging technology. It also examines commonly used targeting mechanisms of optical probes, focusing especially on indocyanine green-the FDA-approved optical dye widely used in clinical settings-and its specific applications in diagnosing and treating liver cancer. Finally, this review highlights the advantages, limitations, and future challenges facing optical molecular imaging technology, offering a comprehensive overview of recent advances, clinical applications, and potential impacts on liver cancer treatment strategies.

Dysfunctional tumor vasculature, hypoxia, and an immunosuppressive microenvironment are significant barriers to effective cancer therapy. Autophagy, which is critical for maintaining cellular homeostasis and apoptosis resistance, is primarily triggered by hypoxia and nutrient deprivation, conditions prevalent in dysfunctional tumor vessels due to poor circulation. However, the role of autophagy in dysfunctional tumor endothelial cells and its impact on treatment and the tumor microenvironment (TME) remain poorly understood. Methods: We used multiplex immunofluorescence and transgene-based imaging to characterize autophagy in endothelial cells from clinical tumor samples, zebrafish xenograft tumors, and murine models. Using a zebrafish xenograft vasculature platform, we analyzed the effects of autophagy inhibitors on the structure and function of the tumor vasculature. In mice, we investigated autophagy inhibition via endothelial-specific autophagy gene knockout (Atg7 ^iECKO) and the autophagy inhibitor SBI-0206965 and evaluated the synergistic effects of combining SBI-0206965 with low-dose chemotherapy (5-fluorouracil, 5-FU) or PD-1 antibody. Human umbilical vein endothelial cells (HUVECs) were cultured in vitro under hypoxic, glucose-deprived, and serum-free conditions to simulate dysfunctional tumor endothelial cells and to explore the mechanisms by which autophagy inhibition optimizes tumor vasculature. Results: Elevated autophagy was observed in tumor endothelial cells within the dysfunctional vasculature. Autophagy inhibition, through either genetic knockout or pharmacological inhibition, selectively prunes dysfunctional vessels and improves vascular function. It also stimulates the formation of a perivascular immune niche, thereby optimizing the tumor immune microenvironment (TiME). Furthermore, combining the autophagy inhibitor SBI-0206965 with low-dose 5-FU or PD-1 antibody potentiated the anti-tumor effects. Mechanistic studies have indicated that autophagy acts as a protective response to the hypoxic and nutrient-deprived TME, while its inhibition, mediated by p53 activation, promotes tumor endothelial cell apoptosis in dysfunctional tumor vessels, further optimizing the structure and function of the tumor vasculature. Conclusions: Targeting endothelial cell autophagy is a promising strategy for remodeling the dysfunctional tumor vasculature, optimizing the TiME, and boosting the efficacy of chemotherapy and immunotherapy.

Ion channels, as functional molecules that regulate the flow of ions across cell membranes, have emerged as a promising target in cancer therapy due to their pivotal roles in cell proliferation, metastasis, apoptosis, drug resistance, and so on. Recently, increasing evidence suggests that dysregulation of ion channels is a common characteristic of cancer cells, contributing to their survival and the resistance to conventional therapies. For example, the aberrant expression of sodium (Na⁺) and potassium ion (K⁺) channels is significantly correlated with the sensitivity of chemotherapy drugs. The endogenous calcium (Ca²⁺) channels contribute to the acquired resistance of osimertinib in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer cell lines. Ferrous ions (Fe²⁺) enhance the sensitivity of breast cancer cells to doxorubicin treatment. Preclinical models have also demonstrated the effect of specific ion channel blockers or modulators on anticancer drug resistance. This review describes the current understanding about the interaction between ion channels and the therapeutic efficacy of anticancer drugs. Then, the therapeutic potential of ion channel blockers or modulators in enhancing the sensitivity or overcoming the resistance of cancer cells to anticancer therapies is discussed. Targeting ion channels will hopefully offer a novel and promising strategy for overcoming cancer drug resistance.

Gene therapy has evolved into a pivotal approach for treating genetic disorders, extending beyond traditional methods of directly repairing or replacing defective genes. Recent advancements in nucleic acid-based therapies-including mRNA, miRNA, siRNA, and DNA treatments have expanded the scope of gene therapy to include strategies that modulate protein expression and deliver functional genetic material without altering the genetic sequence itself. This review focuses on the innovative use of plant-derived nanovesicles (PDNVs) as a promising delivery system for these nucleic acids. PDNVs not only enhance the stability and bioavailability of therapeutic nucleic acids but also improve their specificity and efficacy in targeted gene therapy applications. They have shown potential in the treatment of various diseases, including cancer and inflammatory conditions. By examining the unique properties of PDNVs and their role in overcoming the limitations of conventional delivery methods, this review highlights the transformative potential of PDNV-based nucleic acid therapies in advancing the field of gene therapy.