Theranostics最新文献

Rationale: Dental implant restoration is essential for rehabilitating dentition defects. However, peri-implantitis (PI) seriously threatens the long-term stability of implants. Treating PI requires the complete eradication of plaque biofilm and the meticulous modulation of inflammatory responses. Antibacterial photodynamic therapy (aPDT) presents a promising potential in the antibacterial realm. Nonetheless, traditional aPDT for PI faces challenges such as inadequate biofilm penetration and distribution of photosensitizers, as well as a lack of precise bacteria targeting. Moreover, the excessive ROS generated by aPDT will aggravate the oxidative stress of peri-implant tissues, and this issue cannot be neglected. Methods: The CuTA-Por@ε-PL nanoplatforms (CPP NPs) were synthesized and characterized using dynamic light scattering, transmission electron microscopy, and dye probes in detail. The antibacterial and anti-inflammatory activities of CPP NPs were evaluated both in vitro and in vivo. Moreover, the in vivo therapeutic efficacy was successively analyzed through micro-CT, hematoxylin and eosin staining, Masson's staining, immunofluorescence staining, and colony formation units (CFU), among other techniques. Results: Porphyrin (Por), CuTA nanozyme with SOD/CAT activities, and ε-Polylysine (ε-PL) were combined to fabricate CPP NPs via a straightforward approach. The notable positive charge of CPP NPs facilitated biofilm penetration, distribution and precise bacteria targeting. Then, irradiation with a 660 nm laser triggered a ROS burst for biofilm elimination. After aPDT, CPP NPs scavenged the residual ROS and modulated host immunity by regulating macrophage polarization. As a result, CPP-treated groups demonstrated the most outstanding antibacterial and anti-inflammatory performance in the rat PI model. Conclusions: Given the pathogenesis of PI, this strategy rationally designed a multifunctional NP with antibacterial and anti-inflammatory functions via spatiotemporal ROS regulation. It provides a potentially novel approach for PI treatment, which may have a profound impact on improving the prognosis of patients with PI and advancing the field of implant dentistry.

Background: Aortopathies, such as aortic aneurysm and dissection (AAD), are associated with enhanced aortic wall permeability and endothelial dysfunction. We previously demonstrated that nanoparticle contrast-enhanced computed tomography (nCECT), which detects enhanced aortic wall permeability, could enable non-invasive detection of early AAD before its progresses to fatal aortic rupture. This study investigated the effect of nanoparticle contrast agent (NPCA) size and dose on detection of aortopathy by nCECT. Methods: In vivo studies were performed in a mouse model of sporadic AAD induced by challenging animals with high fat diet (5 weeks) and angiotensin II infusion (last one week). The effects of NPCA size (80, 150, and 240 nm) and NPCA dose (300, 600, and 1200 mg I/kg) on detection of aortopathy were studied. To examine temporal changes in aortic wall NPCA signal at sites of AAD, mice underwent longitudinal CT. To investigate changes in aortic wall integrity, mice underwent follow-up nCECT at 6 months after initial challenge. Imaging findings were compared with gross and histologic examination of the aorta. Fluorescence microscopy was used to confirm presence or absence of intramural NPCA. Results: nCECT using all three sizes of NPCAs demonstrated significantly higher sensitivity (p< 0.05) for the detection of aortopathy compared to gross examination. Histologic analysis showed excellent correlation between the nCECT finding of intramural signal and the presence of aortopathy. The absolute improvements in detection rates were 16%, 20%, and 17% for 80 nm, 150 nm, 250 nm NPCA respectively. Sensitivity of nCECT for detection of aortic injury improved with increasing NPCA dose compared to gross exam (-17% at 300 mg I/kg to 14% at 1200 mg I/kg). Temporal analysis of aortic wall NPCA signal at sites of AAD demonstrated a peak in aortic wall CT attenuation at day 3-5 post-contrast followed by gradual return to baseline by day 120. Follow-up nCECT at 6 months demonstrated absence of wall signal enhancement compared to baseline, suggesting resolution of the altered aortic wall permeability and injury. Histologic analysis demonstrated remodeling and healing of the aortic wall. Conclusions: Nanoparticle contrast-enhanced CT using all three studied nanoparticle sizes demonstrated higher sensitivity than gross examination for the detection of aortopathy. A dose-dependent effect on sensitivity was observed with only high NPCA dose (1200 mg I/kg) demonstrating superior performance compared to gross examination for detecting early stages of aortic injury. Nanoparticle contrast-enhanced CT enabled in vivo interrogation of changes in aortic wall integrity.

Background: Abnormal activation of microglia occurs in the early stage of Alzheimer's disease (AD) and leads to subsequent neuroinflammation and major AD pathologies. Circular RNAs (circRNAs) are emerging as great potential therapeutic targets in AD. However, the extent of circRNAs entwined and the underlying mechanism in microglia-driven neuroinflammation in AD remain elusive. Methods: The circular RNA Dlg1 (circDlg1) was identified using circRNA microarray screening in magnetic-isolated microglia of APP/PS1 mice. CircDlg1 expression in microglia of APP/PS1 mice and AD patients was validated by FISH. Flow cytometry and immunostaining were conducted to explore the roles of circDlg1 in microglia. Adeno-associated virus 9 preparations for interfering with microglial circDlg1 were microinjected into mouse lateral ventricle to explore influences on microglial response, neuroinflammation and AD pathologies. Y-maze, novel object recognition and Morris water maze tasks were performed to assess cognitive performance. RNA pulldown assays, mass spectrometry analysis, RNA immunoprecipitation, and co-immunoprecipitation were performed to validate the underlying regulatory mechanisms of circDlg1. Results: A novel circular RNA circDlg1 was observed elevated using circRNA microarray screening in microglia isolated from APP/PS1 mice and validated increased in intracerebral microglia of AD patients. Microglia-specific knockdown of circDlg1 remarkably ameliorated microglial recruitment and envelopment of amyloid-β (Aβ), mitigated neuroinflammation, and prevented cognitive decline in APP/PS1 mice. Mechanistically, circDlg1 interfered with the interaction between phosphodiesterase 4b (PDE4B) and Smurf2, an E3 ubiquitin ligase of PDE4B. The formed ternary complex protected PDE4B from ubiquitination-dependent degradation via unique N-terminal targeting domain, thus consequently decreasing cAMP levels. We further confirmed that microglial circDlg1 downregulation significantly activated PKA/CREB anti-inflammatory pathway by decreasing PDE4B protein levels in APP/PS1 mice. Conclusion: The novel microglia-upregulated circDlg1 tightly involves in neuroinflammation in APP/PS1 mice via determining the protein fate of PDE4B. Microglial loss of circDlg1 promotes microglial protective response to Aβ deposition and relieves neuroinflammation, thus suggesting a potential therapeutic strategy that specifically targets the microglial response in AD.

Background: Diabetic wounds infected with methicillin-resistant Staphylococcus aureus (MRSA) are challenging to heal due to biofilm formation, which impairs conventional antibiotics with limited penetration and severe side effects. Near-infrared (NIR)-driven nanomotors with autonomous motion and photothermal effects show promise for antibacterial therapy but often lack targeted specificity. Lysostaphin (Ly), an enzyme targeting bacterial cell walls, offers excellent potential against drug-resistant MRSA. Methods: A novel NIR-driven CSIL nanomotor has fabricated by co-loading indocyanine green (ICG) and lysostaphin onto spinous yolk-shell structured C/SiO₂@C nanoparticles. The autonomous motion, biofilm penetration, and antibacterial efficacy of CSIL nanomotors are evaluated in vitro, while their biofilm eradication and wound healing performance are assessed in an MRSA-infected diabetic mouse model using a cascade photodynamic therapy (CPDT) strategy. Results: CSIL nanomotors exhibit photothermal and photodynamic properties with MRSA-targeting specificity. They can effectively eradicate MRSA biofilms both in vitro and in vivo, suppress virulence and biofilm-related genes, thus promoting diabetic wound healing by shaping a microenvironment dominated by M2 macrophages. The CPDT strategy is able to avoid excessive ROS production and thermal damage, enabling safe and effective therapy. Conclusion: CSIL nanomotors, with integrated photothermal, photodynamic, and MRSA-targeting properties, represent a novel, efficient and targeted approach to antibacterial therapy in diabetic wounds, offering significant advantages over conventional antibiotics.

Rationale: The utilization of dissolving microneedles (MNs) facilitates the painless delivery of pharmaceuticals via the transdermal route. However, conventional MNs rely on passive diffusion through the gradual dissolving of the matrix, which can impede the therapeutic efficacy of the delivered drugs. Methods: In this study, we present the development of a novel degradable active MNs platform. This platform employs sodium bicarbonate and citric acid loaded in a dissolving MNs patch as a built-in motor for deeper and faster intradermal payload delivery. The sodium bicarbonate microparticles and citric acid undergo a chemical reaction when in contact with tissue fluid, resulting in the rapid formation of explosive carbon dioxide bubbles. This provides the necessary force to break through dermal barriers and enhance payload delivery. Results: The results demonstrated that the active MNs possessed excellent mechanical properties, rapid detachment characteristics, and superior drug release kinetics. Furthermore, the drug permeation behavior of active MNs exhibited enhanced permeation and distribution in skin-mimicking gel and porcine skin when compared to conventional passive MNs. In vivo experiments employing a rat model of rheumatoid arthritis showed that active MNs achieved superior therapeutic efficacy compared to passive MNs. Conclusions: This universal and effective autonomous dynamic microneedle delivery technology is straightforward to prepare and ultilize, and has the potential to improve the therapeutic efficacy of drugs, offering significant prospects for a diverse range of therapeutic applications.

Rationale: Developing novel pre-operative and intraoperative imaging approaches for glioblastoma multiforme (GBM) could aid therapeutic intervention while sparing healthy normal brain, which remains a significant clinical challenge. 5-aminolevulinic acid (5-ALA) is the only intraoperative imaging agent approved to aid the resection of GBM. Matrix metalloproteinase 14 (MMP14), which is overexpressed in GBM, is an attractive target for preoperative and intraoperative imaging of GBM. Prior studies have shown the feasibility of near-infrared fluorescence (NIRF) imaging and positron emission tomography (PET) imaging of GBM xenografts in mice using MMP-14 targeted peptide probes. The present studies assessed the tumor-specific localization and contrast of these MMP-14 targeted peptides relative to 5-ALA in GBM models. Methods: Fluorescence and PET imaging was performed after i.v. injection of 5-ALA and the MMP-14 targeted peptide probes (non-labeled or radiolabeled with ⁶⁴Cu) in mice bearing human GBM orthotopic xenografts (U87, D54). Imaging signals were correlated to MMP-14 expression determined by immunofluorescence. Tumor-to-normal brain ratio (TBR) and Dice similarity coefficient (DSC) relative to tumor defined by ex vivo pathology or in vivo magnetic resonance imaging were determined for each imaging agent. Results: NIRF signals from the MMP-14 targeted peptide probes showed comparable TBR (p < 0.05) but significantly higher DSC (p < 0.05) relative to 5-ALA. NIRF signals from the peptide probes significantly correlated with MMP-14 expression (p < 0.05). MMP-14 binding peptide labeled with ⁶⁴Cu showed moderate DSC (0.45) while PET signals significantly correlated (p < 0.05) with NIRF signals from a co-injected MMP-14 substrate peptide. NIRF and PET signals localized in residual tumor regions in the resection cavity during in situ resection. Conclusions: MMP-14 targeted peptides showed favorable TBR and higher tumor localization than 5-ALA in GBM orthotopic models. Further development of MMP-14 targeted peptide probes could lead to improved pre-operative and intraoperative management of GBM.

Rationale: Sepsis-induced cardiomyopathy (SIC) is a rapidly progressing condition with poor prognosis in the absence of effective therapeutic interventions. Cardiomyocyte pyroptosis is a critical factor contributing to cardiac dysfunction in SIC. Currently, research on this mechanism remains unclear. Methods: We performed LPS-induced primary mouse cardiomyocyte modeling and mouse SIC modeling. Through mRNA-Seq, we found significant pyroptosis in the cardiac tissue of SIC mice. Further confocal microscopy and immunoprecipitation results confirmed that PTX3 is an important participant in cardiomyocyte pyroptosis. We then used ChIP and dual-luciferase reporter assays to confirm that SOX18 exerts a transcriptional repression effect on PTX3. M6A-Seq and RNA stability assays confirmed that the m6A modification mediated/recognized by RBM15/YTHDF2 is a crucial factor in the changes of SOX18 in SIC. Results: Our experiments demonstrated that the abnormally elevated PTX3 in SIC plays a key role in mediating pyroptosis. Under physiological conditions, PTX3 transcription is repressed by SOX18. However, during septic cardiomyopathy, SOX18 stability is compromised by RBM15/YTHDF2-mediated m6A modification, leading to increased PTX3 levels and the subsequent induction of cardiomyocyte pyroptosis. Conclusion: In summary, we have delineated the RBM15/YTHDF2-SOX18-PTX3 axis in SIC. It provides a new approach for the treatment of cardiomyocyte pyroptosis in SIC and for improving prognosis.

Rationale: Metastatic prostate cancer in the castration-resistant (mCRPC) setting remains challenging to treat. Prostate-specific membrane antigen (PSMA)-targeted alpha therapy (TAT) is emerging as a promising option. We aimed to systematically review the efficacy and safety of PSMA-TAT in patients with prostate cancer. Methods: A comprehensive search of PubMed/MEDLINE and EMBASE databases was conducted up to October 2024, adhering to the PRISMA guidelines. Selected studies were original research articles evaluating the efficacy and/or safety of PSMA-TAT including at least 10 patients. The outcomes measured included any prostate-specific antigen (PSA) response, ≥50% PSA reduction (PSA50), progression-free survival (PFS), overall survival (OS), and adverse events. PSA50 was pooled using a random-effects model, incorporating individual patient data on PSA50 and previous lines of treatment. Results: Eighteen studies involving 1,155 patients met the inclusion criteria. The majority included heavily pre-treated patients. The most commonly employed radiopharmaceutical was [²²⁵Ac]Ac-PSMA-617, in 15 studies. The pooled PSA50 response rate was 65% [95% Confidence interval (CI), 57-72%] with a moderate level of heterogeneity (I² = 81.17%, p < 0.001). Pooled response rates in patients who received none, one, and more than one prior line of treatment were 82% (95% CI, 73-90%), 72% (95% CI, 56-85%), and 55% (95% CI, 48-63%), respectively. PFS varied from 3 to 15 months, and OS from 8 to 31 months. Adverse events were predominantly mild (grades 1-2); severe adverse events (≥ grade 3) included anaemia (11%) and thrombocytopenia (6%). Conclusion: PSMA-TAT holds promising efficacy and an acceptable safety profile for treating metastatic prostate cancer. Randomised controlled trials are needed to optimise treatment protocols toward the implementation of PSMA-TAT into clinical practice.

Retinal images provide a non-invasive and accessible means to directly visualize human blood vessels and nerve fibers. Growing studies have investigated the intricate microvascular and neural circuitry within the retina, its interactions with other systemic vascular and nervous systems, and the link between retinal biomarkers and various systemic diseases. Using the eye to study systemic health, based on these connections, has been given a term as oculomics. Advancements in artificial intelligence (AI) technologies, particularly deep learning, have further increased the potential impact of this study. Leveraging these technologies, retinal analysis has demonstrated potentials in detecting numerous diseases, including cardiovascular diseases, central nervous system diseases, chronic kidney diseases, metabolic diseases, endocrine disorders, and hepatobiliary diseases. AI-based retinal imaging, which incorporates established modalities such as digital color fundus photographs, optical coherence tomography (OCT) and OCT angiography, as well as emerging technologies like ultra-wide field imaging, shows great promises in predicting systemic diseases. This provides a valuable opportunity for systemic diseases screening, early detection, prediction, risk stratification, and personalized prognostication. As the AI and big data research field grows, with the mission of transforming healthcare, they also face numerous challenges and limitations both in data and technology. The application of natural language processing framework, large language model, and other generative AI techniques presents both opportunities and concerns that require careful consideration. In this review, we not only summarize key studies on AI-enhanced retinal imaging for predicting systemic diseases but also underscore the significance of these advancements in transforming healthcare. By highlighting the remarkable progress made thus far, we provide a comprehensive overview of state-of-the-art techniques and explore the opportunities and challenges in this rapidly evolving field. This review aims to serve as a valuable resource for researchers and clinicians, guiding future studies and fostering the integration of AI in clinical practice.

Rationale: LAMP2A is a key translocase in chaperone-mediated autophagy (CMA), and the STING/TBK1 axis is crucial in antitumor immunity. This study explored the complex mechanisms by which CMA regulates the STING/TBK1 degradation and whether targeting LAMP2A could enhance the efficacy of PD-1 monoclonal antibodies. Methods: The expression of STING and TBK1 was detected after treatment with various inhibitors of protein degradation pathways. Confocal microscopy was used to detect the localization of STING and TBK1 in lysosomes. R software was used to analyze LAMP2A expression and prognosis. The biological function of LAMP2A was examined by in vitro and in vivo experiments. Results: Through in vitro and in vivo experiments and a review of clinical specimens, we identified STING/TBK1 as a novel substrate of CMA. Downregulation of LAMP2A enhanced IFNβ production and cellular antiviral response by inhibiting CMA-mediated degradation of STING and TBK1. Based on these observations, further in vivo experiments confirmed that the LAMP2A loss combined with PD-1 monoclonal antibodies significantly stimulated the activation of infiltrating CD8+ T cells, thereby inhibiting tumor growth. Also, non-responder head and neck squamous cell carcinoma (HNSCC) patients undergoing neoadjuvant immuno-chemotherapy had higher levels of LAMP2A and lower levels of PD-L1 expression in their tumor tissues. Conclusions: Our study has revealed a prospective combination therapy, in which diclofenac functioning as a LAMP2A inhibitor, enhances the anti-tumor efficacy of PD-1 monoclonal antibody by inhibiting the degradation of STING and TBK1.