Theranostics最新文献

Rationale: Traumatic brain injury (TBI) poses a significant global health concern, necessitating a comprehensive understanding of its pathophysiology to devise effective treatments. The correlation between the intensity of head impact during injury and resultant neuropathology and behavioral changes in TBI remains unclear. Methods: The Quantitatively Controlled and Measured-TBI (QCM-TBI) system, a novel closed-head injury model, enables precise control and measurement of impact during collision. The QCM-TBI system is designed with a unique gravity-compensating animal support system that replicates natural head motion in human TBI. Using QCM-TBI in conjunction with a multimodal sensor fusion technique, we measured instantaneous force over the time of collision, while compensating distortion led by extreme acceleration of the force sensor. To address whether TBI affects neuropathology and behaviors of mice in a force-dependent manner, we conducted transcriptome analysis, electron microscopy, and confocal microscopy in QCM-TBI model. We further compared molecular and pathological features of QCM-TBI mice with chronic traumatic encephalopathy (CTE) patients. Results: Transcriptome analysis of QCM-TBI mice showed a significant downregulation of neuronal genes associated with synaptic function and neurogenesis, particularly in the hippocampus, which correlated with the severity of neuropathological features. Molecular and neuropathological characteristics of QCM-TBI mice partially resemble those of chronic traumatic encephalopathy (CTE) patients. Levels of phosphorylated Tau (p-Tau) and amyloid precursor protein (APP) correlate with impact magnitude, while neurofilament levels diminish in QCM-TBI mice. Neurons exhibit ultrastructural axonal damage in an impact-dependent manner. Conclusions: Overall, this study suggests head impact intensity leads to decreased adult hippocampal neurogenesis, increased levels of phosphorylated Tau (p-Tau), and axonal damage, reflecting key neuropathological signatures of traumatic brain injury. Consequently, therapeutic strategies for TBI should account for the impact's severity in determining neuropathological outcomes.

Rationale: Osteoarthritis (OA) lacks disease-modifying therapies. Although systemic denosumab delays OA progression, it causes uneven drug distribution and off-target effects, whereas intra-articular injections are invasive and risk joint infection. We aimed to develop a minimally invasive microneedle platform that delivers denosumab locally to achieve therapeutic efficacy comparable to intra-articular injection while avoiding systemic exposure. Methods: A dissolvable denosumab-loaded microneedle array (MNs@De) was fabricated for transcutaneous intra-articular delivery. OA was induced in rodents and Beagle dogs; animals were treated with MNs@De, systemic denosumab, intra-articular denosumab, or vehicle. Synovial inflammation, cartilage erosion, and pain were evaluated histologically and behaviorally. Single-cell RNA sequencing and immunofluorescence were performed to assess macrophage senescence and chondrocyte metabolism. Secretion of pro-inflammatory and catabolic factors was quantified in vitro using senescent macrophage-chondrocyte co-cultures. Results: MNs@De delivered denosumab effectively into joints, significantly reducing synovial inflammation, cartilage erosion, and pain compared with systemic administration and achieving outcomes comparable to intra-articular injection. Single-cell profiling revealed that denosumab markedly decreased senescent macrophage abundance within synovial tissue. Mechanistically, denosumab inhibited senescent macrophage-derived pro-inflammatory and catabolic factor release, thereby shifting chondrocytes from catabolic to anabolic states. Conclusions: Targeting senescent macrophages via MNs@De attenuates OA progression without requiring intra-articular injections or increasing systemic drug exposure. Microneedle-mediated denosumab delivery offers a minimally invasive, localized therapeutic strategy for OA.

Mitochondria are involved in energy production, signal conduction, and cellular differentiation in the human body, and they determine the direction of tumorigenesis and development. Mitochondria-targeted therapy in cancer cells has been reported since researchers discovered the relationship between mitochondria and cancer. However, the complexity of the tumor microenvironment (TME) can impair the therapeutic effect. Understanding the mechanisms of mitochondrial function in various cells of TME (e.g., tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs), T cells, natural killer (NK) cells, tumor-associated neutrophils (TANs)), as well as mediated crosstalk with cancer cells, would be beneficial for accelerating these therapeutic strategies into clinical practice and leading to more effective disease treatment. Subsequently, we summarized representative small-molecule drugs targeting mitochondrial homeostasis, energy metabolism, and mitochondrial DNA (mtDNA) and evaluated their limitations. Building on this foundation, we reviewed the latest multifunctional nanomedicines. These agents leverage TME responsiveness, surface-targeting engineering, and multimodal synergy (combining chemotherapy, photodynamic therapy (PDT), sonodynamic therapy (SDT), radiodynamic therapy (RDT), and immunotherapy) to precisely deliver drugs, ions, genetic material, and even whole mitochondria to target organelles. This approach simultaneously remodels the immunosuppressive microenvironment and induces immunogenic cell death (ICD).

Rationale: Acute glaucoma is triggered by sudden spikes in intraocular pressure, which induces retinal ischemia/reperfusion (RI/R), leading to hypoxia, oxidative stress, and ultimately PANoptosis in retinal ganglion cells (RGCs). Developing a therapeutic approach that simultaneously targets these events may offer a promising strategy for reducing secondary neuronal damage in acute glaucoma. Methods: We developed a reactive oxygen species (ROS)/hypoxia dual-responsive, biodegradable nanoparticle system (NPs) containing azo and thioketal bonds, designed to encapsulate melatonin (MT), a known endogenous antioxidant and PANoptosis inhibitor. The biocompatibility, biosafety, and therapeutic efficacy of MT-NPs were evaluated in vitro using an oxygen-glucose deprivation/reperfusion (OGD/R) R28 cell model and in vivo using a RI/R rat model. Results: The NPs efficiently released encapsulated MT in response to hypoxic conditions and the presence of ROS. This controlled-release system improved both the biocompatibility and long-term retention of MT in the retina. MT-NPs effectively alleviated hypoxia, cleared excess ROS, and inhibited PANoptosis in RGCs following acute glaucomatous injury. Compared to direct MT administration, MT-NPs were more effective at protecting RGC axons and somas and facilitating restoration of visual function in rats with acute glaucoma. Conclusion: This simplified but multifunctional delivery system leveraged the widely available and safe compound melatonin in a highly efficient nanoparticle platform. This system offers potent neuroprotective effects to the retina preventing injury caused by acute glaucoma, and thereby providing a promising clinically translatable strategy for the treatment of glaucoma.

Rationale: Myocardial ischemia-reperfusion (I/R) injury remains a major clinical challenge that limits the efficacy of reperfusion therapy in acute myocardial infarction, mainly due to excessive production of reactive oxygen species (ROS) and the resulting oxidative stress, inflammation, and cardiomyocyte death. However, conventional antioxidant strategies show limited clinical efficacy, highlighting the urgent need for novel redox-regulating therapies. Methods: We synthesized carbon dot nanozymes (SM-CDs) via a green hydrothermal process using Salvia miltiorrhiza, a traditional Chinese medicinal herb. Their size, structure, and antioxidant enzymatic activities were thoroughly characterized. The contribution of surface functional groups to the superoxide dismutase (SOD)-like activity of SM-CDs were investigated by surface modification. In vitro antioxidant, anti-inflammatory, and anti-apoptotic effects were evaluated in RAW264.7 macrophages and H9C2 cardiomyocytes. In vivo therapeutic effects were accessed in a rat myocardial I/R model. Transcriptomics analysis was used to explore underlying cardioprotective mechanisms. Network pharmacology analysis was employed to study potential pharmacological activity inherited from the herbal precursor. Results: SM-CDs exhibit potent ROS-scavenging capacity, with surface carbonyl and hydroxyl groups playing key roles in their remarkable SOD-like activity. In vitro, SM-CDs effectively scavenged intracellular ROS, suppressed macrophage M1 polarization, and attenuated cardiomyocyte apoptosis. In vivo, intramyocardial injection of SM-CDs significantly reduced inflammation, apoptosis, and infarct size, while improving cardiac remodeling and functional recovery through fibrosis inhibition and enhanced neovascularization. These effects were potentially associated with inhibition of NF-κB and NOD-like receptor signaling pathways and activation of PI3K-Akt and FoxO pathways. Strong pathway concordance between SM-CD-regulated pathways and known therapeutic targets of Salvia miltiorrhiza suggests that SM-CDs may retain pharmacological activity from their herbal precursor. Conclusions: This study introduces SM-CDs as biocompatible nanozymes with potent antioxidant and cardioprotective potential for myocardial I/R injury.

Background: The healing of chronically infected wounds is severely hindered by persistent inflammation, bacterial infection, and oxidative stress, posing great challenges to clinical therapy. To address these challenges, we designed a multifunctional dual-layer microneedles patch (MN@DOX+RES) featuring reactive oxygen species (ROS) responsiveness and dual drug delivery capabilities. This patch is engineered to deliver synergistic antibacterial, anti-inflammatory, and antioxidant effects, thereby promoting the healing of infected wounds. Methods: The dual-layer microneedles patch comprises a rapidly dissolvable HA backing layer loaded with DOX and a ROS-responsive tips layer composed of a crosslinked AHA-PBA/PVA matrix that encapsulates water-soluble RES inclusion complexes. A series of in vitro experiments was conducted to evaluate the mechanical strength, biocompatibility, antibacterial activity against Staphylococcus aureus and Escherichia coli, antioxidant performance, and macrophage polarization. In vivo evaluations were performed on rat models with infected skin wounds. Results: The MN@DOX+RES microneedles exhibited strong skin penetration ability and excellent mechanical strength. It significantly inhibited bacterial growth, efficiently scavenged free radicals, reduced intracellular ROS levels, and enhanced M2 macrophage polarization. In vivo, the patch accelerated wound closure, suppressed the inflammatory cytokine IL-6, enhanced IL-10 expression, and activated the Keap1/Nrf2/HO-1 antioxidant signaling pathway. Conclusions: This study proposes an innovative therapeutic strategy that combines dual-drug delivery, oxidative microenvironment regulation, and immune modulation to promote the healing of chronic infected wounds. The MN@DOX+RES microneedles system demonstrates great potential in overcoming clinical challenges associated with infection, inflammation, and the limitations of conventional therapeutic approaches.

Rationale: Emerging evidence implicates the gut microbiota in epilepsy pathogenesis through the microbiota-gut-brain axis, yet the functional contribution of specific microbial taxa to epileptogenesis remains unclear. This study aimed to investigate whether Lachnospira eligens (L. eligens) can alleviate epileptic activity by modulating the gut-brain axis, with a focus on intestinal barrier integrity, blood-brain barrier (BBB) integrity, and neuroimmune responses. Methods: Using a cobalt wire-induced rat epilepsy model, we performed fecal 16S rDNA sequencing to assess gut microbiota alterations. Rats received daily oral gavage of L. eligens or PBS for 15 days, with colonization confirmed by qPCR. Seizure activity was monitored using long-term video electroencephalogram (EEG) and Racine scores. Barrier function, systemic inflammation, and microglial activation were assessed using FITC-dextran (FD-4, 4 kDa) assay, Western blotting (WB), immunohistochemistry (IHC), immunofluorescence (IF), ELISA, and qPCR. Serum short-chain fatty acids (SCFAs) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Epileptic rats exhibited early gut microbiota dysbiosis, with a significant decline in Lachnospira abundance both preceding and succeeding seizure onset (P = 0.041, P = 0.026). L. eligens stably colonized the gut (Day 6 and Day 15, both P < 0.001). Supplementation significantly reduced grade 4-5 seizure frequency (P = 0.002) and prolonged seizure latency (P = 0.005). Barrier integrity improved, as indicated by lower plasma FD-4 (P < 0.001), increased colonic (WB: P = 0.013; IHC: P = 0.003) and cortical occludin expression (WB: P = 0.002; IHC: P = 0.01), and decreased serum lipopolysaccharide-binding protein (LBP) (P = 0.011). Neuroinflammation was attenuated, including reduced microglial activation (P = 0.048), lower pro-inflammatory cytokines (IL-1β, P = 0.047; IL-6, P = 0.001; TNF-α, P = 0.002), and decreased M1 polarization (P = 0.004). Serum butyrate increased (P = 0.014), and SCFAs, especially butyrate, suppressed lipopolysaccharide (LPS)-induced iNOS (P = 0.031) in BV2 cells. Conclusions: These findings demonstrate that L. eligens mitigates epileptic activity by restoring intestinal barrier and BBB integrity and suppressing neuroinflammation. Our study highlights L. eligens as a promising microbiota-based intervention for epilepsy through modulation of the gut-brain axis.

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disorder that typically affects young adults and is primarily characterized by demyelinating lesions in the central nervous system (CNS). According to the Revised McDonald Criteria, the clinical diagnosis of MS can be established based on a combination of clinical observations, the presence of focal lesions in at least two distinct CNS areas on magnetic resonance imaging (MRI) and the detection of specific oligoclonal bands in the cerebrospinal fluid. Conventional MRI remains a cornerstone of MS diagnosis and disease monitoring, providing high-resolution assessments of lesion burden and brain atrophy. In addition, advanced MRI methods are increasingly applied in research settings to probe myelin integrity, iron deposition, and biochemical changes, with the potential to complement established diagnostic workflows in the future. Despite remarkable advances in the management of MS over the past two decades, complex differential diagnoses and the lack of effective imaging tools for therapy monitoring remain major obstacles, thus channeling the development of innovative molecular imaging probes that can be harnessed in clinical practice. Indeed, positron emission tomography (PET) has a significant potential to advance the contemporary diagnosis and management of MS. Given the solid body of evidence implicating myelin dysfunction in the pathophysiology of MS, myelin-targeted imaging probes have been developed, and are currently under clinical evaluation for MS diagnosis and therapy monitoring. In parallel, ligands for the 18 kDa translocator protein (TSPO) and the cannabinoid receptor type 2 (CB2R) have been employed to capture neuroinflammatory processes by visualizing microglial activation, while other tracers allow the assessment of synaptic integrity across various disease stages of MS. Further, PET probes have been employed to delineate the role of activated microglia and facilitate the assessment of synaptic dysfunction across all disease stages of MS. This review discusses the challenges and opportunities of translational molecular imaging by highlighting key molecular concepts that are currently leveraged for diagnostic imaging, patient stratification, therapy monitoring and drug development in MS. Moreover, we shed light on potential future developments that hold promise to advance our understanding of MS pathophysiology, with the ultimate goal to provide the best possible patient care for every individual MS patient.

Rationale: The efficacy of radiotherapy in triple-negative breast cancer (TNBC) is often limited by an immunosuppressive tumor microenvironment (TME), requiring high radiation doses that cause systemic toxicity. There is a critical need for theranostic strategies capable of guiding therapy and amplifying the efficacy of low-dose radiation. Methods: We developed a multifunctional organolutetium nanosensitizer (LSPA) for image-guided, low-dose radioimmunotherapy. Lutetium (Lu) serves as both a contrast agent for CT imaging and a radiosensitizer through the generation of reactive oxygen species (ROS). The LSPA nanoparticles were engineered to selectively accumulate in tumors and release their therapeutic payload in response to the acidic TME. Results: At a low 6 Gy X-ray dose, LSPA synergized with the PARP inhibitor Olaparib to induce extensive DNA damage. This activated the cGAS-STING pathway and remodeled the TME. The treatment promoted immunogenic cell death, dendritic cell maturation, and M1 macrophage repolarization. It also decreased regulatory T cells, leading to increased CD4⁺ and CD8⁺ T cell infiltration in both primary and metastatic tumors. Conclusion: This theranostic strategy suppressed primary and distant (abscopal) tumors, prevented recurrence, and established durable immune memory with low-dose irradiation. Our findings present a clinically translatable approach that combines a nanosensitizer with PARP inhibition to turn immunologically "cold" tumors into "hot" ones, thereby enhancing the efficacy of low-dose radioimmunotherapy while limiting systemic toxicity.

Rationale: The integration of biological and physical interventions represents a promising therapeutic strategy for spinal cord injury (SCI), offering a novel approach to restore disrupted motor pathways. This study investigates whether repetitive transcranial magnetic stimulation (rTMS) can prevent cerebral neuroapoptosis and promote the regeneration and integration of brain-derived nerve fibers with neural network tissueoids (NNToids) following SCI. Methods: Neural stem cell-derived NNToids were transplanted into rats with complete SCI and simultaneously treated with 10 Hz rTMS. Neuroinflammatory responses, neuroapoptosis, neuronal activation, and axonal regeneration were systematically evaluated using transcriptomic sequencing, histological validation, Western blotting, and neural tract tracing. The responsiveness of NNToids to 10 Hz rTMS in facilitating motor neural pathway reconstruction was also assessed. Results: 10 Hz rTMS significantly enhanced cFOS expression in layer V pyramidal neurons of the sensorimotor cortex (SMC), markedly reduced microglial activation and neuroapoptosis, and upregulated the expression of mitochondrial-related protein TOM20, axonal regeneration marker p-S6, and synaptic plasticity-associated protein Arc in SMC neurons. NNToids facilitated the ingrowth of corticospinal tract (CST) and 5-hydroxytryptamine (5-HT) - positive nerve fibers into the transplantation site. Retrograde PRV tracing demonstrated that 10 Hz rTMS enhanced the capacity of NNToid neurons to relay CST and 5-HT signals to hindlimb motor neurons. Functional assessments and cortical motor evoked potentials confirmed that the rTMS-NNToid combination improved the transmission of motor-related neural signals to the hindlimbs. Histological analysis further demonstrated that activated NNToid neurons exhibited increased expression of N-methyl-D-aspartate receptors (NMDAR) and formed more synaptic connections with vGluT-positive axon terminals. Conclusion: These findings demonstrate that rTMS mitigates motor cortex inflammation, promotes the regeneration and integration of brain-derived nerve fibers with NNToid neurons, thereby establishing a foundation for motor function recovery. Moreover, the study identifies the mechanism through which NNToid neurons mediate motor neural pathway reconstruction under rTMS modulation. Although based on a rat model, this work provides a promising framework for future biophysical therapies that combine patient-derived autologous iPSC-based NNToids with non-invasive brain stimulation.