Theranostics最新文献

Rationale: Clinical trials for Alzheimer's disease (AD) often yield inconsistent results despite promising preclinical findings. Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), a cortisone reductase, has demonstrated neuroprotective effects in preclinical models. However, clinical outcomes have varied. A potential explanation is the limited representation of apolipoprotein E ε4 (APOE4) carriers in preclinical studies, despite evidence that APOE4 alters stress responses and glucocorticoid regulation. We hypothesized that APOE4 status modulates the efficacy of HSD11B1 inhibition by influencing cortisol metabolism and AD pathology. Methods: We conducted a genetic association study to test whether HSD11B1 variants are linked to plasma cortisol levels, brain atrophy, and AD risk, stratified by APOE4 status. Postmortem human brain tissues and wild-type mice were analyzed for HSD11B1 expression, with emphasis on the entorhinal cortex (EC). Neuroimaging data were examined to assess correlations between cortisol levels and brain volume. In cell models, recombinant APOE4 protein was tested for regulation of HSD11B1 expression via the transcription factor C/EBPβ and its effect on neuronal cortisol production. Results: We identified a functional HSD11B1 variant associated with elevated cortisol, increased AD risk, and accelerated EC atrophy, specifically in APOE4 carriers. HSD11B1 was significantly upregulated in the EC of APOE4-positive brains. Mechanistic studies demonstrated that APOE4, but not APOE3, upregulates HSD11B1 via C/EBPβ, thereby increasing neuronal cortisol. Conclusions: These findings explain the inconsistent efficacy of 11β-HSD1 inhibitors in AD patients by revealing an APOE4-dependent activation of HSD11B1 that promotes early EC pathology. They also support genotype-guided therapeutic strategies targeting local cortisol metabolism.

Advances in patient-derived cancer models are pushing precision oncology by linking functional testing directly to therapeutic decision-making. Traditional two-dimensional (2D) cancer cell culture systems have long served as accessible tools for studying cancer biology and drug responses, but their inability to replicate the complexity of the tumor microenvironment limits their translational value. In recent years, advances in culture and imaging technologies have enabled the development of three-dimensional (3D) cancer models, such as spheroids, organoids, and patient-derived explants, that more accurately represent tumor architecture and behavior in vivo. These models better capture cell-cell and cell-ECM interactions and allow to study immune-tumor dynamics, providing critical insights into therapeutic efficacy and drug resistance of chemotherapies, targeted therapies, and immunotherapies. Notably, the integration of 3D modeling with functional precision medicine approaches, such as ex vivo drug screening using patient-derived samples, has opened new avenues for individualized cancer treatment. Coupling these advanced models with advanced imaging readouts for spatially resolved and functional analysis further transforms them into quantitative theranostic platforms that link biological mechanisms to clinical decision-making. In this review, we explore the evolution from 2D to 3D cancer models, examine their respective advantages and limitations, and highlight their role in advancing functional precision oncology and immuno-theranostics.

Rationale: NF2-related schwannomatosis (NF2-SWN) is a progressive neurological disorder with a hallmark of bilateral vestibular schwannomas (VSs), leading to irreversible hearing loss and reduced quality of life. To date, the FDA has not approved any pharmacological therapies for treating VS or hearing loss. While radiotherapy (RT) is the standard treatment for growing VSs, it often exacerbates hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, their efficacy in non-malignant tumors like VS remains largely unexamined. Methods: We used immune-competent VS mouse models to assess the efficacy of combined anti-PD1 (αPD1) and RT treatment, tumor growth, and hearing preservation. Results: We found three significant therapeutic benefits: i) RT induces immunogenic cell death and activates the STING pathway, enhancing αPD1 efficacy and generating long-term immune memory, ii) The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) RT to peripheral nerve tumor induces a systemic abscopal effect, which enhances αPD-1 efficacy to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury. Conclusion: Our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS and NF2-SWN.

Background: In many disorders, metabolic and inflammatory derangements that originate in peripheral organs have a deleterious impact on the brain. Brain functional impairment, defined as hepatic encephalopathy, is one of the main diagnostic criteria for acute liver failure (ALF), a severe complication of acute liver injury (ALI). While brain inflammation (neuroinflammation) and metabolic alterations significantly contribute to hepatic encephalopathy, their non-invasive evaluation remains challenging. Methods: To address this limitation, we utilized dual radiotracer [¹⁸F]-fluoro-2-deoxy-2-D-glucose ([¹⁸F]FDG) and [¹¹C]-peripheral benzodiazepine receptor ([¹¹C]PBR28) microPET imaging followed by conjunction analysis and metabolic connectivity mapping. We applied this advanced methodology in mice with high dose acetaminophen (N-acetyl-p-aminophenol, APAP)-induced ALI, which can progress into ALF. Results: We observed hepatocellular damage, liver and systemic inflammation, and increased density of hippocampal microglia in mice with ALI. MicroPET imaging analysis characterized the presence of brain region-specific neuroinflammation and altered brain energy metabolism in mice with ALI. We also identified both gains and losses in connectivity, as well as a dual role of neuroinflammation. These results revealed brain "neuroinflammetabolic" signatures of ALI. Conclusion: These findings provide a platform for non-invasively diagnosing early signs of hepatic encephalopathy with the goal of informing timely diagnoses and targeted therapies. Our approach can be further utilized in non-invasive brain assessments in liver diseases and other disorders classically characterized by peripheral immune and metabolic dysregulation.

Rationale: Evidence accumulating across experimental studies and clinical settings supports a central role for the C5a-C5aR signaling axis in promoting tumor progression and immune evasion. Nevertheless, whether a vaccination approach targeting C5a can elicit robust anti-tumor immune responses and suppress tumor growth has not yet been investigated. This research aimed to develop an efficient B-cell peptide epitope vaccine targeting the C5a-C5aR pathway for cancer therapy. Methods: Chimeric C5a B-cell peptide epitope vaccines were synthesized using high-performance liquid chromatography (HPLC), and C5a antibodies titers were determined using enzyme-linked immunosorbent assay (ELISA). Multiple mouse tumor models were employed to evaluate the vaccine's efficacy. The mechanisms of MAX449 were assessed through in vitro and in vivo approaches, incorporating single-cell RNA sequencing (scRNA-seq), flow cytometry, western blotting, real-time quantitative PCR, transwell migration assays and ELISA. Results: The vaccine MAX449 could induce high titer of C5a antibodies and effectively suppress tumor growth in multiple mouse models. Furthermore, MAX449 significantly boosted the effectiveness of anti-PD1 therapy. It not only inhibited the migration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment through downregulating CCRL2 expression via the NF-κB signaling pathway but also reduced the immunosuppressive function of PMN-MDSCs by decreasing IL-1β production through the same pathway. Following vaccine administration, a significant expansion of anti-tumor CD8⁺ T cells was observed. Most importantly, the vaccine proved to augment the antitumor efficacy of programmed death-1 (PD-1) antibodies in cold and hot tumor mouse models. Conclusions: This research demonstrated that MAX449 induced C5a antibodies, which block C5a-C5aR pathway in PMN-MDSCs, suppression of their migratory and immunosuppressive functions, and consequent antitumor activity. Meanwhile, MAX449 boosted the therapeutic efficacy of PD-1 antibody in hot and cold tumor model mice. This study provides compelling evidence supporting the clinical evaluation of MAX449 as an innovative therapeutic approach for cancer.

Background: Chronic exposure to free fatty acids (FFAs) and glucose may disrupt metabolic homeostasis and initiate pathological processes. This study investigated the effects of hyperglycemia and fat overload on renal endoplasmic reticulum (ER) stress, pyroptosis and fibrogenesis in mice and the underlying basis. We hypothesized that the combined insult would more severely induce Gα₁₂-dependent ER stress and renal complications. Methods: Mice were subjected to either high fat diet (HFD)+streptozotocin (STZ), or STZ treatment, and AZ2 was used as an anti-diabetic agent. Blood sera were used for blood biochemistry, and tissues were employed for RNA sequencing, immunoblottings, TEM, histology and immunohistochemistry. HEK293 and other cells were used for high glucose (HG) and palmitate treatment, or Gα₁₂ or siGα₁₂ transfection. Results: The combined HFD and STZ treatment, showing enrichment of genes related to GPCR signaling, inflammasome, ER stress, and pyroptosis in the RNA-sequencing analysis, upregulated Gα₁₂ in the kidney, alongside increased PGC1α and PPARα. IRE1α and ATF6 were elevated without an increase in GRP78. This was accompanied by elevated blood glucose, creatinine, and BUN levels. We also found increases of pro-IL-1β, IL-1β, caspase-1, and NLRP3, demonstrating pyroptosis. Immunoassays revealed increased fibrosis markers. AZ2 reversed these changes. STZ treatment alone exhibited mild complications in the absence of Gα₁₂ induction despite severe hyperglycemia. In cell-based assays, HG+palmitate elicited IRE1 activation along with Gα₁₂ overexpression although HG alone had a minimal effect. Overexpression of Gα₁₂ facilitated the effect of HG+palmitate on ER stress, pyroptosis, and fibrosis, whereas Gα₁₂ knockdown had the opposite effect, as corroborated by the outcomes obtained using STZ-treated Gα₁₂-/-, Gα₁₂+/-, and Gα₁₃ liver-specific KO mice. Conclusion: These findings support the role of HG and lipid overload combination in driving renal pyroptosis and fibrogenesis through Gα₁₂-mediated ER stress and inflammasome, delineating the mechanism underlying the conditions of diabetic renal complications and pharmacological intervention.

Myocardial infarction (MI) is a leading cause of death in the United States. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) present a promising strategy for regenerating the damaged heart tissue post-MI. However, poor cell engraftment and survival remain significant barriers in their effective use for myocardial repair. In this study, we developed a "cardiac patch" using a bi-layered, aligned coaxial patch for epicardial delivery of hiPSC-CMs in a preclinical porcine MI model. The cardiac patch (40 mm in diameter and 500 µm thick) was fabricated using polycaprolactone (PCL) and gelatin via electrospinning and seeded with twenty-two million hiPSC-CMs. In vitro functional assessment showed synchronized contractility of the hiPSC-CMs along the aligned fibers. The in vivo transplantation of the cardiac patch was performed in a translationally relevant preclinical large animal (porcine) MI model at 1-week after MI induction. Histological assessments showed successful engraftment and survival of the hiPSC-CMs at the infarct, up to 4-weeks after cardiac patch-transplantation. This was accompanied by modest improvements in LVEF (Patch:18.0% vs Control: -1.2%) and a decrease in the enhancement percentage (Patch: 28.8% vs Control: 18.6%) at 4-weeks post-patch transplantation. Additionally, absence of arrhythmias or teratoma formation, affirmed the safety of the cardiac patch. Overall, we have demonstrated the feasibility, safety and engraftment of bi-layered aligned cardiac patches seeded with hiPSC-CMs in preclinical porcine MI model as a promising therapeutic approach for myocardial regeneration post-MI.

Glioblastoma (GBM) is an aggressive brain tumor characterized by limited therapeutic efficacy and challenges in accurate imaging, largely due to its invasive growth, drug resistance, and the restrictive blood-brain barrier (BBB) hindering the delivery of both therapeutic and diagnostic agents. Current GBM treatments and imaging approaches often suffer from insufficient agent penetration into the tumor. Additionally, they frequently exhibit toxicity or poor signal-to-noise ratios. Polysaccharide (PSC)-based polymers, with their inherent biocompatibility, biodegradability, and versatile chemical modifiability, offer a promising platform to overcome these limitations. These natural polymers can be engineered into sophisticated nanocarriers that enhance BBB traversal, enable targeted tumor accumulation of therapeutic payloads and imaging agents Furthermore, they facilitate controlled drug release and improve diagnostic signal generation. Consequently, PSC-based systems can improve therapeutic efficacy and enhance diagnostic accuracy for tumor visualization. Furthermore, they reduce systemic side effects and support multimodal strategies, ranging from single-modality interventions to integrated theranostic systems. This review aims to comprehensively discuss recent advancements, current challenges, and future perspectives of PSC-based nanomedicines in GBM therapy and imaging.

Rationale: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy. The metastasis and poor prognosis of ESCC are closely associated with tumor microenvironment (TME) heterogeneity, which is driven by epithelial-mesenchymal transition (EMT). Clinically, how to diagnose and target EMT progression remains a key challenge for ESCC. Methods: Integration of pathological images and bulk RNA sequencing profiles identified a high-risk subtype exhibiting EMT enrichment and immunosuppression. Single-cell and spatial transcriptomics revealed EMT macrostates and their spatial distribution. The role of CACNA1C in programming malignant phenotype was tested in vitro. A pathological image-based deep learning model successfully predicted the spatial expression distribution of CACNA1C, indicating possible clinical utility. Results: EMT progression comprised three macrostates: the early state (high epithelial and metastatic potential), the stable state (hybrid E/M phenotype and high stemness), and the late state (high mesenchymal and invasive propensity). ITGA3 and ITGB4 antagonistically regulate malignant phenotype in the early state. Notably, suppression of CACNA1C induced transdifferentiation from stable/late-state cells to normal epithelium-like cells. Conclusions: This study provides novel insights into the EMT mechanism in ESCC, proposes an intervention strategy, and emphasizes the promising clinical application of pathological images in EMT assessment.

Rationale: The anatomical complexity and restricted regenerative potential of alveolar bone defects create a significant clinical challenge and highlight the need for spatially biomimetic and biologically supportive biomaterials. Methods: We developed a bone-mimicking matrix hydrogel scaffold inspired by the features of a "flowerbed," utilizing machine learning-guided three-dimensional bioprinting. Gelatin methacrylate (GelMA), decellularized bone matrix (DBM), and urine-derived stem cell exosomes (USC-Exos) were co-integrated during the printing process to deliver crucial biophysical and biochemical signals for bone regeneration. Results: The GelMA/DBM/USC-Exos scaffold exhibited high printing fidelity, enabling precise fabrication of defect-specific geometries while preserving exosome bioactivity and achieving sustained release (> 16 days). Functionally, the scaffold promoted M2 macrophage polarization and markedly upregulated osteogenic and angiogenic gene expression, which was approximately 2-fold higher than that of the control (p < 0.01). Mechanistically, the scaffold enhanced oxidative phosphorylation by activating the AMP-activated protein kinase pathway, resulting in a nearly 2-fold increase in adenosine triphosphate content and promoting the osteogenic differentiation of jawbone marrow-derived mesenchymal stem cells. In vivo implantation in mandibular defect models induced robust neovascularization and bone formation, resulting in a nearly 3-fold increase in vessel density and 65.6 ± 3.0% new bone volume after 4 and 8 weeks, respectively, effectively promoting coordinated and functional alveolar bone regeneration. Conclusions: This study establishes a biomimetic approach that integrates structural biomimicry, exosome-mediated bioactivity, and energy metabolism regulation, offering a promising and targeted strategy for personalized alveolar bone regeneration.