Theranostics最新文献

Rationale: Messenger RNA (mRNA)-based cancer vaccines hold great potential as immunotherapeutic agents; however, their clinical translation remains hindered by inefficient systemic delivery, suboptimal antigen presentation, and formulation-associated toxicity of lipid nanoparticles (LNPs). To address these issues, we sought to design a delivery platform that couples antigen expression and innate immune stimulation within a single nanostructure. Methods: We engineered a synthetic immuno-ribonucleocarbohydrate (iRNC) system constructed from fluorinated cyclodextrin nanoparticles. This modular platform co-delivers mRNA and small-molecule NFκB agonists, enabling simultaneous antigen expression and immune activation. Using ovalbumin (OVA) mRNA as a model antigen, we evaluated biodistribution, immune activation, and therapeutic efficacy in CT2A orthotopic glioblastoma models following systemic administration. Results: iRNCs were preferentially internalized by tumor-associated phagocytes, leading to efficient mRNA transfection and antigen presentation within the glioblastoma microenvironment. This dual-function system elicited robust innate immune activation with minimal systemic toxicity. Importantly, iRNC vaccination demonstrated both prophylactic and therapeutic efficacy in CT2A-bearing mice, significantly suppressing tumor growth and extending survival compared to conventional LNP formulations. Conclusion: The iRNC platform unifies mRNA delivery and immune stimulation into a single, programmable nanoparticle, providing a distinct and clinically relevant strategy for systemic mRNA vaccination. Its ability to reprogram tumor-associated phagocytes and induce potent anti-tumor immunity underscores its promise as a next-generation platform for cancer immunotherapy.

THz technology is expected to provide breakthroughs for precision oncology due to its physical nature, such as non-ionizing radiation nature, sensitivity to water and fingerprint recognition. Yet, its clinical application is severely limited due to their drawbacks: shallow penetration depth, difficult interpretation and sensitivity. This review examines recent interdisciplinary advances that integrate THz technology with materials science, nanotechnology, artificial intelligence (AI), computational modeling, gene editing, and microfluidics to develop intelligent diagnostic and therapeutic systems capable of supporting the full oncology continuum-from tumor imaging and biomarker detection to treatment monitoring and drug delivery assessment. For example, combining THz with metamaterials or nanostructures enhances sensitivity for trace-level biomarker detection; AI algorithms enable rapid, accurate interpretation of complex spectral data for automated diagnosis; and convergence with microfluidics and CRISPR-based systems has led to ultra-sensitive liquid biopsy platforms. These integrated approaches not only address existing technical barriers but also open pathways toward multifunctional theranostic systems with practical clinical utility. By fostering cross-disciplinary collaboration, THz technology can be further optimized to enable more accurate, effective, and personalized cancer care, transforming its potential from foundational research into real-world clinical impact.

Rationale: Myeloid cells, including neutrophils (Nu), monocytes (Mo) and macrophages (Mac), rapidly accumulate after ischemic cardiac injury where they play integral roles in inflammation and repair. β2-adrenergic receptor (β2AR) signaling regulates numerous facets of immune cell behavior, but its impact on myeloid cell-specific responses to acute cardiac injury is unclear. Methods: Myeloid cell-specific β2AR knockout (LB2) and control mice were subjected to myocardial infarction (MI) with or without prior transplantation with shRNA-modified bone marrow. The impact of myeloid cell-specific β2AR deletion, and mechanistic basis for the effect, were assessed via echocardiography, immunohistochemistry, flow cytometry, gene expression and efferocytosis analyses. Results: LB2 mice displayed better cardiac function and less fibrotic remodeling post-MI. Despite a similar initial influx of myeloid cell subtypes, by 4 days post-MI LB2 mice had significantly reduced Nu, concurrent with increased Nu-containing Mac, indicating an enhanced efferocytosis capacity. Indeed, the pro-efferocytotic protein annexin A1 (AnxA1) was elevated in several β2AR-deficient myeloid cell types following MI. Mechanistically, we found the expression of several miRs known to repress Anxa1 expression were elevated in response to β2AR stimulation, an effect absent with β2AR deletion, and miR-374b-5p mimic in particular was sufficient to decrease Anxa1 expression. Finally, lentivirus-encoded shRNA was used to induce knockdown of Anxa1 expression in the bone marrow of LB2 mice prior to MI, which reduced Nu efferocytosis in vitro and prevented the ameliorative effects on cardiac fibrosis and function observed with LB2 mice following MI in vivo. Conclusion: Myeloid cell-specific β2AR deletion leads to loss of miR-374b-5p-mediated repression of AnxA1, which allows for enhanced efferocytosis-mediated Nu clearance, thereby limiting infarct expansion and improving post-injury cardiac function and fibrotic remodeling.

Background: Cancer immunotherapies have shown remarkable efficacy in advanced malignancies, yet many patients remain unresponsive. This variability, along with concerns about adverse effects and healthcare costs, highlights the need for predictive biomarkers and physiologically relevant cancer models to forecast individual treatment responses. Existing systems inadequately recapitulate the human tumor microenvironment (TME), which is essential for understanding immune-tumor interactions and treatment efficacy. Here, we developed an ex vivo 3D human tissue culture model that preserves the native TME for functional immunotherapy testing. Such a short-term culture platform also supports functional precision medicine by enabling rapid ex vivo assessment of therapeutic responses to guide clinical decisions. Methods: Fresh, intact human lymph node (LN) tissue pieces were cultured in optimized perfusion bioreactors for three days, during which CAR T cell therapies and antibody-based treatments were administered. Post-culture analyses were performed using flow cytometry, histology, and multiplexed fluorescence microscopy. Results: The bioreactor system significantly improved tissue viability compared to traditional plate cultures. Novel CAR T cells with enhanced PI3K signaling exhibited superior tissue infiltration but showed comparable cytotoxicity to conventional CAR T cells. Pembrolizumab, a PD-1 inhibitor, significantly reduced lymphoma and melanoma cell viability without affecting benign LN tissues. Conclusions: This optimized bioreactor culture system provides a robust platform for evaluating immunotherapy efficacy within a physiologically relevant TME. It offers valuable potential for advancing personalized treatment strategies, accelerating the understanding of immunotherapy mechanisms, and improving clinical outcomes.

Rationale: Non-target lesions (NTLs) progression is common in patients with coronary artery disease (CAD). However, its predictors remain obscure. Methods: An angiographic study was conducted in patients with CAD who underwent coronary angiography twice at an interval of 6 to 30 months. NTLs were defined as lesions not treated with percutaneous coronary intervention (PCI) during the first hospitalization. A stenosis index (SI) was calculated from all NTLs in each patient. NTLs progression was defined as an increase in SI (ΔSI > 0) at follow-up. Results: Among 1658 patients recruited, 1061 (64.0%) exhibited NTL progression, with a ΔSI of 0.75 (0.40, 1.30) over a mean follow-up period of 13 months. The NTLs progression group had more males, diabetics, higher neutrophil ratio, creatinine, fasting blood glucose (FBG), uric acid, more PCI therapy and higher SI on the first admission, and higher systolic blood pressure, heart rate, serum levels of low-density lipoprotein cholesterol and FBG at readmission. Multiple logistic regression analysis identified male sex, PCI therapy, and SI on the first admission, and FBG on the second admission were independent predictors of NTLs progression, with the odds ratio of 1.390 (95%CI 1.034~1.869), 1.375 (95%CI 1.087~1.740), 1.003 (95%CI 1.002~1.004) and 1.184 (95% CI 1.086~1.291), respectively. Conclusions: Over 60% of CAD patients developed NTL progression within 30 months. Male sex, PCI therapy and SI on the first admission, and FBG on the second admission were independent predictors of NTLs progression.

Renal ischemia-reperfusion injury (RIRI) mainly comes from inflammation and oxidative stress. Treating with inflammation monotherapy or oxidative stress monotherapy can't reduce RIRI. This study involved the synthesis of Panax notoginseng-derived carbon dots (PN-CDs) herbzymes, nanozymes from Chinese herbal medicines, exhibiting inherent antioxidant enzymatic activity. The diverse surface functional groups facilitate the effective scavenging of reactive oxygen species (ROS) and suppress the expression of inflammatory factors. In the RIRI model, PN-CDs demonstrated extended systemic circulation and improved renal targeting, effectively decreasing renal tissue concentrations of neutrophil gelatinase-associated lipocalin (NGAL), creatinine, blood urea nitrogen, and kidney injury molecule-1 (KIM-1). They also decreased inflammatory factors and lipid peroxidation markers, thereby mitigating renal damage. Multi-omics analysis showed that PN-CD protects kidney function mainly via gut microbiota, shrinking nephrotoxins such as indoxyl sulfate and enhancing beneficial metabolisms such as β-indol-3-acetamide and stimulating pathways like aryl hydrocarbon receptor (AHR), ERK to reduce inflammation and oxidative stress. In conclusion, PN-CDs herbzyme was a potential treatment for RIRI and provided the theoretical basis for the herbzyme therapy of kidney disease, as well as the proof-of-concept for the gut-kidney axis.

Surgical management of head and neck squamous cell carcinoma (HNSCC) patients often requires resection of the deep cervical lymph nodes. Fluorescence guided surgery (FGS) is a growing area of oncologic surgery that has shown promise for this purpose, however, it is limited by the signal penetration through the neck. To address this, we sought to evaluate the efficacy of the anti-EGFR antibody [¹¹¹In]panitumumab to detect metastatic lymph nodes both on preoperative imaging and intraoperatively. We hypothesized that the addition of a radiolabeled antibody would be safe and effective in detecting malignant tissue when given alone or together with the optical agent panitumumab-IRDye800CW (pan800). Methods: Seventeen patients were enrolled and received 5 mCi of [¹¹¹In]panitumumab with nine patients (53%) receiving [¹¹¹In]panitumumab and pan800. SPECT/CT scans were performed prior to surgical resection. Intraoperatively, patients underwent gamma tracing and the patients who received pan800 also underwent optical fluorescence imaging. Resected specimens were compared to final histopathology to determine the sensitivity and specificity of the two tracers. Results: No adverse events related to the [¹¹¹In]panitumumab were reported. SPECT/CT performed 3 days post-injection showed higher tumor-to-blood pool ratio compared to earlier scans (p = 0.04), and when compared to pathological assessment, could detect disease greater than 1 cm in diameter. Intraoperatively, resection of the primary tumor resulted in a significant drop in gamma counts (p < 0.001). In vivo detection of metastatic lymph nodes using the radiotracer was inconsistent and attributed to high background counts as patients who underwent surgery before 48 hours post-injection had significantly higher precordial counts than patients who underwent surgery after 48 hours, even when corrected for time, weight, and dose (p = 0.04). Ex vivo, metastatic lymph nodes had gamma counts almost twice that of benign (p < 0.0001). The separately dosed pan800 and [¹¹¹In]panitumumab showed strong co-localization within metastatic lymph nodes (R = 0.87). Conclusion: Intravenous infusion of [¹¹¹In]panitumumab in HNSCC patients is safe, whether administered alone or with pan800. Consistent with other studies, ex vivo application of the radiotracer differentiated tumor containing tissue from benign. However, intraoperative use of the radiotracer to detect metastatic lymph nodes was limited by background signal at early timepoints and signal decay at later timepoints.

Recent breakthroughs in radiopharmaceutical (RP) therapy have emerged interest in employing Auger electron (AE)-emitting radionuclides as potential agents for precise theranostics. AE provides energy with exceptional localization due to their short tissue penetration range (TPR, < 10 nm), rendering them particularly effective for targeting nuclear DNA in tumor cells. In this context, AE-emitting radionuclide therapy (AE-emitting RLT) enables the targeted destruction of tumor cells while reducing harm to adjacent healthy tissue, a significant challenge in this field. Preclinical and early clinical investigations reveal the efficacy of AE-emitting RLTs in the theranostics of diverse malignancies, such as glioblastoma, prostate cancer, and neuroendocrine tumors. Notwithstanding these developments, challenges and limitations persist regarding dosimetry, delivery efficiency, and the treatment of radiotoxicity. A new paradigm is being developed to tackle the obstacles encountered by integrating molecular target markers (e.g., PARP) that function near the nucleus to improve the intranuclear delivery efficiency of AE-emitting radionuclides. Novel radiochemical methods such as these have facilitated the more stable and efficient labeling of biomolecules with AE-emitting radionuclides. Also, recent advances in DNA-molecular targeting, nanoparticles, nucleic acid/protein engineering, click- or bioorthogonal conjugation chemistry, and artificial intelligence (AI)-based structure modeling present concrete opportunities to overcome these limitations. Moreover, the integration of diagnostic imaging companion platforms employing theranostic radioisotope pairings facilitates real-time assessment of therapeutic efficacy and biodistribution, resulting in the formulation of enhanced treatment regimens. This review summarizes the prior development, recent advancements, barriers in clinical implementation, and future perspective of AE-emitting RLTs.

Efferocytosis, phagocytic clearance of apoptotic cells (ACs), is an essential biological process that resolves inflammation and regulates tissue regeneration in various organ systems. Through removal of apoptotic cell debris, efferocytosis attenuates secondary necrosis and dampens the release of damage-associated molecular patterns (DAMPs). More importantly, it can reprogram phagocytes towards a pro-reparative phenotype via the secretion of anti-inflammatory mediators, metabolic rewiring, and the production of growth factors. There are four closely regulated stages in the entire process: "find-me" signal-mediated phagocyte recruitment, recognition of ACs via "eat-me" signals, AC internalization via Rho GTPase-dependent actin remodeling, and phagolysosomal degradation of ACs by either canonical or light chain 3 (LC3)-associated phagocytosis (LAP). In a repair context, efferocytosis may refer to the clearance of dying cells during various tissue repair processes, such as wound healing, liver injury, myocardial infarction, intestinal damage, kidney injury and muscle injury. Efferocytosis regulates inflammation resolution, stem/progenitor cell activation, extracellular matrix remodeling, and angiogenesis to coordinate tissue repair. Chronic pathology (e.g., diabetic ulcers, fibrosis) induced by dysfunctional efferocytosis results from accumulation of non-phagocytosed ACs that maintain inflammation and impair regeneration. Therapeutic strategies targeting dysfunctional efferocytosis have been developed, encompassing active pharmaceutical ingredients, biologics, and biomaterials-assisted therapeutic modalities. Despite promising outcomes from preclinical studies, challenges still exist in the spatiotemporal control and clinical translation of these therapeutic strategies. Future research could focus on the multi-omics integration and smart biomaterial development to dynamically modulate efferocytosis during different disease phases.

Rationale: Loss of histone deacetylase 5 (HDAC5) is frequently observed in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC), and is associated with poor patient survival. Although HDAC5 has been implicated in DNA damage repair, the molecular mechanisms by which it regulates DNA double-strand break (DSB) repair pathway choice remain unclear. Methods: Using PDAC cell lines, genetically engineered mouse models, patient-derived organoids, and biochemical assays, we investigated the role of HDAC5 in DNA end resection and homologous recombination (HR). Protein interactions, post-translational modifications, DNA repair pathway activity, and cellular responses to DNA damage and PARP inhibition were systematically analyzed. Results: We identify HDAC5 as a critical regulator of DNA end resection and HR through deacetylation of Ku70. DNA damage induces casein kinase 2 (CK2)-mediated phosphorylation of HDAC5, promoting its nuclear translocation. Nuclear HDAC5 directly deacetylates Ku70 at lysine 287, facilitating Ku70 dissociation from DSB sites, thereby enabling DNA end resection and HR repair. In contrast, HDAC5 loss or CK2 inhibition results in Ku70 K287 hyperacetylation, prolonged retention of the Ku heterodimer at DSBs, impaired DNA end resection, and suppression of HR. Consequently, HDAC5-deficient PDAC cells exhibit increased sensitivity to PARP inhibitors, while pharmacological CK2 inhibition sensitizes HDAC5-proficient tumors to PARP inhibition. Conclusions: These findings uncover a previously unrecognized CK2-HDAC5-Ku70 signaling axis that governs DNA repair pathway choice by regulating DNA end resection. Targeting this axis provides a mechanistic rationale for enhancing PARP inhibitor sensitivity in PDAC, including tumors without classical homologous recombination deficiency.