Theranostics最新文献

Malignant tumors have been a serious threat to human health with their increasing incidence. Difficulties with conventional treatments are toxicity, drug resistance, and recurrence. For this reason, non-invasive treatment modalities such as photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), and others have received much attention. Among them, Ferrocene (Fc)-based nanomedicines for enhanced Chemodynamic Therapy (ECDT) is a new therapeutic strategy based on the Fenton reaction. Based on ferrocene's good biocompatibility, potentiation in medicinal chemistry, and good stability of divalent iron ions, scientists are increasingly using it as a Fenton's iron donor for tumor therapy. Such ferrocene-based ECDT nanoplatforms have shown remarkable promise for clinical applications and have significantly increased the efficacy of CDT treatment. Ferrocene-based nanomedicines exhibit exceptional consistency owing to their low toxicity, high stability, enhanced bioavailability, and a multitude of advantages over conventional approaches to cancer treatment. As a consequence, a number of tactics have been investigated in recent years to raise the effectiveness of ferrocene-based ECDT. In this review, we detail the different forms and strategies used to enhance Ferrocene-based ECDT efficiency.

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.

The interplay between multiple organs, known as inter-organ crosstalk, represents a complex and essential research domain in understanding the mechanisms and therapies for kidney diseases. The kidneys not only interact pathologically with many other organs but also communicate with other systems through various signaling pathways. It is of paramount importance to comprehend these mechanisms for the development of more efficient therapeutic strategies. Despite extensive research in IgA nephropathy (IgAN), the most common kidney disease, the elaboration mechanism of IgAN remains challenging. Numerous studies suggest that alterations in the intestinal microbiome and its metabolites are pivotal in the progression of IgAN, opening new avenues for understanding its mechanisms. Interestingly, certain presumed probiotics, such as Akkermansia muciniphila, have been implicated in the onset of IgAN, making the exploration of gut microbiota in the context of IgAN pathogenesis even more intriguing. In this review, we summarize the status of gut microbiology studies of IgAN and explore the possible mechanisms and intervention prospects. Future research and treatment directions may increasingly emphasize systemic, multi-organ combined interventions to decelerate the advancement of kidney disease and enhance the overall prognosis of patients.

Rationale: Mutations in the synaptic protein MAM domain containing glycosylphosphatidylinositol anchor 2 (MDGA2) have been associated with autism spectrum disorder (ASD). Therefore, elucidating the regulatory mechanisms of MDGA2 can help develop effective treatments for ASD. Methods: Liquid chromatography-tandem mass spectrometry was carried out to identify proteins interacting with the extracellular domain of RPS23RG1 and with MDGA2, followed by co-immunoprecipitation assays to confirm protein-protein interactions. RPS23RG1 and SORT1 levels were downregulated by siRNAs to study their effects on MDGA2 degradation, with additional applications of immunoblotting and immunostaining assays. Lysosome isolation was performed to determine the lysosomal degradation of MDGA2 further. Rps23rg1 knockout mice and Mdga2 ^+/- mice were subjected to various behavioral tests to study their ASD-like phenotypes. AAVs expressing MDGA2 were delivered in Rps23rg1 knockout mice, and RPS23RG1-derived peptide was delivered in Mdga2 ^+/- mice to study their rescuing effects. Results: We found that both RPS23RG1 and SORT1 interacted with MDGA2. MDGA2 was primarily degraded through the SORT1-mediated lysosomal degradation pathway. RPS23RG1 competed with SORT1 for MDGA2 binding to inhibit MDGA2 degradation. Furthermore, we showed that Rps23rg1 knockout mice exhibited decreased MDGA2 levels and ASD-like behaviors, whereas restoration of MDGA2 levels attenuated social defects in Rps23rg1 KO mice. Moreover, we identified a crucial region of RPS23RG1 for MDGA2 interaction and found that a peptide derived from this region not only bound MDGA2 and promoted MDGA2 levels, but also rescued social defects in Mdga2 ^+/- mice. Conclusion: Our findings highlight a crucial role of RPS23RG1 in antagonizing SORT1-mediated lysosomal degradation of MDGA2 and suggest a potential for targeting the RPS23RG1-MDGA2 axis to treat ASD with MDGA2 deficiency.

Rationale: Cancer remains a leading cause of mortality, with aggressive, treatment-resistant tumors posing significant challenges. Current combination therapies and imaging approaches often fail due to disparate pharmacokinetics and difficulties correlating drug delivery with therapeutic response. Methods: In this study, we developed radionuclide-activatable theranostic nanoparticles (NPs) comprising folate receptor-targeted bimetallic organo-nanoparticles (Gd-Ti-FA-TA NPs). Polyvalent tannic acid was used to coordinate titanium (Ti), a reactive oxygen species (ROS)-generating catalyst, gadolinium (Gd), a magnetic resonance imaging (MRI) contrast agent, and cypate, a near-infrared fluorescent dye. Results: The NPs exhibited higher magnetic field-dependent relaxivities (r ₁ = 20.8 mM⁻¹s⁻¹, r ₂ = 72.1 mM⁻¹s⁻¹) than Gd-DTPA (r ₁ = 4.8 mM⁻¹s⁻¹, r ₂ = 4.9 mM⁻¹s⁻¹) on a 3 T MRI scanner. Tannic acid coordination reduced the Ti band gap from 3.3 eV in TiO₂ NPs to 2.0 eV, tripling ROS generation under UV light exposure. In breast cancer models (4T1 and PyMT-Bo1), Cerenkov radiating radiopharmaceuticals activated Gd-Ti-FA-TA NPs in vitro and in vivo, generating cytotoxic ROS to inhibit tumor cell viability and prevent tumor progression. In vivo, the NPs selectively accumulated in 4T1 tumors and enhanced both T₁ and T₂ MRI contrast, highlighting a strategy to locally activate cytotoxic ROS generation with radiopharmaceuticals for cancer treatment, utilizing cross-modality PET/MRI and optical imaging for shallow and deep tissue visualization. Conclusion: The integrated nanoplatform allows direct imaging of drug delivery, providing guidance for the optimal timeline to activate therapeutic effects of pro-theranostic NPs via external triggers such as radionuclide-stimulated dynamic treatment.

Rationale: This study investigates a method for programming immune cells using a biomaterial-based system, providing an alternative to traditional ex vivo cell manipulation techniques. It addresses the limitations of engineered adoptive T cell therapies, such as T cell exhaustion, by introducing a gelatin-hyaluronic acid (GH-GMA) hydrogel system. Methods: We characterized tonsil mesenchymal stem cells (TMSCs), lymphatic endothelial cells (T-LECs), stimulated T-CD8⁺ T cells (STCs), and GH-GMA biomaterials. The 10% 5:1 GH-GMA hydrogel, loaded with anti-CD28, cytokines interleukin-2 (IL-2) and vascular endothelial growth factor C (VEGF-C), forms a functional hydrogel capable of releasing these immune-stimulating factors. T-LEC spheroids, derived from tonsil mesenchymal stem cells (TMSCs), were encapsulated within the hydrogel to act as antigen-presenting cells for T cells. Results: Co-encapsulation of STCs and T-LEC spheroids in the functional hydrogel resulted in significant expansion and enrichment of STCs during cultivation. Moreover, when cancer cells were co-encapsulated with STCs and T-LECs, there was increased migration of STCs towards the cancer cells and elevated expression of PD-L1 on the cancer cells. Conclusions: These findings suggest that the GH-GMA hydrogel, combined with anti-CD28, IL-2, VEGF-C, and T-LEC spheroids, enhances T cell activity, presenting a promising platform for cancer immunotherapies and modulation of the suppressive tumor microenvironment.

[This corrects the article DOI: 10.7150/thno.86103.].