Theranostics最新文献

Central nervous system (CNS) diseases are challenging to treat because of the blood-brain barrier (BBB), formed by tight junctions that limit the transcellular transport of therapeutic drugs. Carbon dots (CDs) have emerged as versatile nanotheranostic platforms for the targeting, diagnosis, and treatment of CNS diseases owing to their ultrasmall size, intrinsic photoluminescence, tunable surface chemistry, and biocompatibility. Surface modifications of CDs with targeting ligands, polymer coatings, biomimetic membranes, and exosome-like molecules enable BBB penetration and selective brain accumulation. CDs also support multimodal imaging techniques, such as fluorescence, magnetic resonance, and photoacoustic imaging, for early disease detection and real-time therapeutic monitoring. In addition, their ability to deliver drugs, genes, and therapeutic agents, combined with their antioxidant, anti-inflammatory, photothermal, photodynamic, and sonodynamic properties, highlights their potential for the integrated diagnosis and treatment of CNS diseases. This review systematically summarizes the background of CDs, the design of BBB-penetrating CDs, and their applications in tumor diagnosis, treatment, and imaging-guided cooperative therapies for CNS diseases. Finally, current obstacles and future perspectives are discussed. This review provides a valuable reference for the rational design of BBB-penetrating CDs for the precise treatment of neurological disorders and brain cancers.

Metal-organic frameworks (MOFs) are a unique class of porous materials constructed from metal-containing nodes, known as secondary building units (SBUs) and organic ligands. Their highly tunable structures enable the encapsulation of a broad range of therapeutic agents, spanning small-molecule chemotherapeutics to biomacromolecules such as proteins, DNA, and RNA. By rational selection of metal ions and organic linkers, diverse functionalities, including molecular imaging and phototherapeutic capabilities, can be included into MOFs, rendering them promising nanoscale platforms of nanomedicines. In this review, we summarize recent advances of MOFs for drug delivery, cancer imaging and theranostics. We discuss the progress in regulating the morphology and functions of MOFs through diverse synthetic strategies and surface modification approaches. We further systematically analyzed and discussed MOFs in the applications of drug delivery, molecular imaging, and cancer theranostics, with recent strategies. Finally, key limitations associated with the clinical translation of MOFs are discussed, along with the corresponding bottlenecks, future challenges, and emerging opportunities.

[This corrects the article DOI: 10.7150/thno.108875.].

Background: As a member of the oxysterol-binding protein-like (OSBP) family, which is primarily involved in lipid transport and metabolic regulation, Oxysterol-binding protein-like protein 3 (OSBPL3), has garnered increasing attention due to its abnormal expression and functional roles in various cancers. However, the specific role and molecular mechanisms of OSBPL3 in pancreatic cancer (PDA) remain unclear.

Methods: Single-cell and spatial transcriptomic data analyses combined with functional experiments were utilized to systematically evaluate OSBPL3 expression changes at various stages of PDA. Cell lines with decreased or increased expression of OSBPL3 were generated to analyze its role in cell proliferation, stemness, metastasis and chemoresistance. Single-cell transcriptomic and mass spectrometry data was further integrated with functional validation to explore the regulatory mechanisms through which OSBPL3 modulates PDA malignancy.

Results: OSBPL3 was highly expressed throughout various stages of pancreatic inflammation, precursor lesions, and PDA in both human and mouse pancreatic tissues. Increased OSBPL3 expression significantly enhanced the proliferative capacity and stemness of PDA cells, and promoted their migration, invasion, and metastasis. Moreover, increased OSBPL3 expression impacted on the malignant behaviors of PDA, e.g., reduced PDA cell sensitivity to oxaliplatin, whereas inhibition of NOTCH pathway significantly attenuated the drug resistance and stemness features induced by increased OSBPL3 expression, suggesting that OSBPL3 modulated PDA malignancy via oncogenic pathways such as NOTCH signaling pathway. Furthermore, increased OSBPL3 expression was significantly associated with the enrichment of cholesterol esters and other steroid metabolites, as well as their related pathways. Inhibition of key enzymes involved in cholesterol synthesis resulted in a significant reduction in NOTCH pathway and stemness in PDA in vivo mouse models.

Conclusions: Aberrant expression of OSBPL3 plays a pivotal role in PDA initiation and progression and serves as an independent prognostic factor for poor outcomes in PDA patients. OSBPL3 promotes PDA cell proliferation, stemness, and chemoresistance by mediating lipid metabolic reprogramming and regulating oncogenic pathways such as NOTCH. Therefore, inhibition of OSBPL3 expression or blockade of its signaling represent a potential therapeutic strategy to improve therapeutic efficacy and prognosis in PDA patients.

Rationale: Therapy resistance remains a critical challenge in colon adenocarcinoma (COAD). The dysregulation of programmed cell death (PCD) pathways significantly influences therapeutic response, but its integrated role in shaping the tumor microenvironment (TME) and driving clinical heterogeneity in COAD is poorly defined.

Methods: We established a Programmed Cell Death-related Subtype (PCDS) classification by integrating 12 PCD pathways across transcriptomic data from 1,140 COAD patients using non-negative matrix factorization (NMF). The subtypes were validated in independent RNA-sequencing cohorts. We characterized the genomic, TME, and therapeutic features of each PCDS using multi-omics data analysis, and computational drug repositioning. Molecular docking and in silico drug sensitivity analyses were employed to evaluate candidate drugs.

Results: We identified three robust subtypes, including PCDS1 (immune-activated), PCDS2 (WNT and TP53 signaling activation), and PCDS3 (mesenchymal and T-cell dysfunction/exclusion). PCDS3, enriched with inflammatory cancer-associated fibroblasts (iCAFs), exhibited the poorest prognosis and dual resistance to both chemotherapy and immunotherapy (>80% non-response). Analysis of single-cell and spatial transcriptomics data revealed the activation of MDK-SDC2 ligand-receptor axis between tumor cells and fibroblasts in PCDS3, spatially associated with T-cell dysfunction and exclusion. Computational drug repositioning identified the sunitinib as having selective potency against PCDS3 tumors, showing significantly lower IC50 values and high-affinity binding to SDC2 in molecular docking.

Conclusions: This study defines a novel molecular subtype for COAD, linking PCD dysregulation to distinct TME remodeling and therapeutic outcomes. Targeting the MDK-SDC2 axis with agents such as sunitinib may offer a promising strategy to overcome stromal-mediated immunotherapy resistance in the most lethal PCDS3 tumors.

Background: Lactate accumulation exacerbates the severity of sepsis-associated acute kidney injury (SA-AKI), although the mechanism remains unclear. Since pyroptosis contributes to renal tubular epithelial cell (RTEC) death during SA-AKI, this study explores whether lactate exacerbates pathogenesis by promoting RTEC pyroptosis.

Methods: The clinical correlation between lactate and SA-AKI was examined using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database and patient samples. Lactate's role in RTEC pyroptosis was evaluated in lipopolysaccharide (LPS)-exposed HK-2 cells and in cecal ligation and puncture (CLP)-induced mice. Cross-analyzing bioinformatics and RNA-seq data from LPS/lactate-exposed HK-2 cells revealed pyroptosis genes associated with SA-AKI. Molecular mechanisms were explored via Western blot, ELISA, mitochondrial function assays, chromatin immunoprecipitation (ChIP), and co-immunoprecipitation (co-IP). High-throughput drugs screening was conducted to identify candidates acting on the Sphingosine kinase 1(SPHK1)/Sirtuin 1(SIRT1) axis, which were validated in vitro and in vivo.

Results: Lactate aggravated SA-AKI by promoting RTEC pyroptosis. Bioinformatic and functional studies identified SPHK1 as the key mediator. Both SPHK1 knockdown and its inhibitor PF-543 alleviated lactate-augmented pyroptosis. Drug screening identified nicotinamide adenine dinucleotide (NAD⁺), which simultaneously suppressed SPHK1 expression and the RTEC injury marker kidney injury molecule-1 (KIM-1). Combining NAD⁺ and PF-543 synergistically attenuated SA-AKI. Sepsis-induced lactate accumulation promoted P300-mediated histone H3 lysine 18 lactylation (H3K18la) at the SPHK1 promoter, epigenetically enhancing its transcription. SPHK1 then phosphorylated and degraded SIRT1, inducing peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) hyperacetylation, thereby impairing SIRT1/PGC-1α signaling and triggering NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-driven pyroptosis. Reciprocally, SIRT1 acted as a delactylase delactylase to reduce H3K18la and inhibit SPHK1 transcription, forming a SPHK1-SIRT1 negative feedback loop.

Conclusions: The study identifies an H3K18la-mediated SPHK1-SIRT1 axis as a key factor of RTEC pyroptosis in SA-AKI. The combined pharmacological strategy of NAD⁺ supplementation and SPHK1 inhibition represents a promising therapeutic strategy for SA-AKI.

Rationale: Regulatory T (Treg) cells suppress autoimmunity and restrain inflammatory responses, showing promising potential in autoimmune glomerulonephritis (GN) therapy with minimizing nonspecific immunosuppression. Although low-dose interleukin-2 (IL-2) has been shown to promote Treg expansion, its clinical utility is constrained by its short half-life and concurrent effector T cell activation.

Methods: An IL-2 mutein STS718 was engineered by introducing point mutations and fusing it to a human IgG1 Fc domain. The molecular characteristics of STS718, including its affinity, selectivity, and half-life were evaluated. In vivo expansion of Treg cells by STS718 was assessed in mice and cynomolgus monkeys. Experimental autoimmune GN models, including crescentic GN and membrane GN, were established to test the therapeutic potential of STS718. The ability of STS718 to induce human functional Treg cells was confirmed using human naïve CD4⁺ T cells from donors and peripheral blood mononuclear cells (PBMCs) from autoimmune GN patients.

Results: STS718 exhibited a lower affinity for IL-2 receptor (IL-2Rβγ) and comparable affinity for IL-2Rαβγ compared with wild-type IL-2-Fc of human, rat, and mouse, as well as a prolonged half-life. STS718 expanded Treg cells in mice and cynomolgus monkeys in a manner that was dependent on either time or dose, without significantly affecting the effector T cell activation. Proof-of-concept experiments confirmed that sustained Treg expansion mediated by STS718 effectively suppressed the progression of autoimmune GN models, exhibiting superior efficacy compared to wild-type IL-2-Fc. In addition, the STS718 was capable of inducing the expansion of human functional Treg cells from either naïve CD4⁺ T cells of healthy donors or PBMCs from autoimmune GN patients.

Conclusions: Collectively, these findings suggest that engineered IL-2 mutein which selectively expands Treg cells in vivo holds significant promise as an alternative immunotherapeutic strategy for controlling autoimmune GN while reducing nonspecific immunosuppression.

Rationale: Glucocorticoid (GC)-associated osteonecrosis of the femoral head (GONFH) is an incurable orthopedic illness. Reduced osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is at the core of the pathogenesis of GONFH; however, its molecular mechanism remains unclear. The study aimed to explore the pathological mechanisms of GONFH and to investigate the efficacy and mechanism of naringenin (NAR) in treating GONFH.

Methods: RNA sequencing was conducted to investigate the pathogenesis of GONFH and identify the potential therapeutic mechanism of NAR. The levels of autophagy, ferroptosis, apoptosis, and osteogenesis were examined in clinical, animal, and BMSC samples. Moreover, the specific binding of NAR to ULK1 and its role in promoting ser757 phosphorylation of ULK1, leading to reduced autophagy-dependent cell death and increased osteogenic differentiation of BMSCs, were investigated using molecular dynamics simulations and systematic in vivo and in vitro experiments.

Results: In clinical, animal, and BMSCs samples, autophagy, ferroptosis, and apoptosis were notably increased in the GONFH group, while osteogenesis was markedly decreased. In addition, the effects of rapamycin (RAPA, an autophagy agonist) and 3-methyladenine (3-MA, an autophagy inhibitor) were investigated to confirm that the GC-induced decrease in osteogenic differentiation of BMSCs is mediated through autophagy-dependent cell death. Additionally, NAR exhibits high affinity for ULK1, which increases its inhibitory phosphorylation at ser757. This particular communication inhibits GC-induced autophagy and subsequent cell death, thereby normalizing osteogenic differentiation of BMSCs. It is interesting to note that the protective effects of NAR were abolished by pharmacological (RAPA) and genetic (ULK1-S757A mutation) interventions.

Conclusions: Taken together, our work elucidates a pathogenic process involving autophagy-dependent cell death and defines NAR as a specific treatment that regulates ULK1 to halt this pathogenic cascade.

[This corrects the article DOI: 10.7150/thno.53572.].

Rationale: Deciphering the molecular consequences of protein cleavage in inflammatory signaling is vital for defining the mechanisms of intestinal autoinflammation and identifying new therapeutic targets for inflammatory bowel disease (IBD). While it was previously established that HOIL-1 cleavage by MALT1 negatively regulates NF-κB activation and inflammatory responses in vitro, the pathophysiological role of HOIL-1 cleavage in regulating intestinal inflammation and the specific function of the resulting C-terminal fragment (C-HOIL-1) remained elusive. This study aimed to define the role of HOIL-1 cleavage and C-HOIL-1 in modulating gut inflammation.

Methods: To investigate the impact of HOIL-1 cleavage on intestinal inflammation, the global and myeloid-specific transgenic mouse models with uncleavable HOIL-1 (lacking C-HOIL-1) were established, and their disease phenotypes and immune profiles were characterized under DSS-induced colitis. Genetically engineered THP-1 monocytic cells expressing uncleavable HOIL-1 and C-HOIL-1 were constructed to elucidate the molecular mechanisms of C-HOIL-1 in regulating inflammatory signaling. Finally, Lenti-C-HOIL-1 was delivered to the colon of wild-type mice via enema to evaluate the therapeutic potential of C-HOIL-1 in controlling intestinal inflammation.

Results: Mice with uncleavable HOIL-1 (lacking C-HOIL-1) present a more severe disease phenotype in DSS-induced colitis; specifically, the infiltration of inflammatory monocytes, M1-type macrophages, and neutrophils is significantly elevated in the colon. Mechanistically, we discover that C-HOIL-1 has novel biological functions in i) inhibiting NF-κB signaling, ii) interacting with STAT1 to down-regulate STAT1-mediated inflammatory signaling, and iii) up-regulating ARG1 expression. Collectively, these actions suppress the inflammatory responses in monocytes/macrophages, and impede the differentiation of M1-type macrophages. The pretreatment of Lenti-C-HOIL-1 to the colon of wild-type mice alleviates DSS-induced intestinal inflammation.

Conclusions: Our results define the pathophysiological role of HOIL-1 cleavage in colitis, and unveil new functions of C-HOIL-1 in regulating myeloid inflammatory responses. These findings provide a potential therapeutic strategy for controlling gut inflammation in IBD.