Theranostics最新文献

Developing therapies for complex brain diseases faces significant challenges due to biological complexity and the stringent blood-brain barrier. While nanomedicine holds promise, traditional R&D paradigms suffer from inefficiency. This review introduces an intelligent theranostic paradigm that integrates high-fidelity brain organoid models, high-throughput screening (HTS/HCS), and Artificial Intelligence (AI). In this closed-loop workflow, organoid platforms serve a diagnostic role, generating predictive data on nanomedicine performance. AI then provides therapeutic guidance by processing this data to drive rational drug design, synthesis, and interaction prediction. This AI-driven convergence is poised to significantly accelerate the development of precisely targeted and individualized nanomedicines, offering new hope for breakthroughs in treating brain diseases.

Pharmacological treatment of brain diseases is hampered by the blood-brain barrier that prevents the vast majority of drugs from entering the brain. For this reason, the pharmaceutical industry is reluctant to invest in the development of new neurotropic drugs. Even if effective pharmacological strategies for the treatment of brain diseases will be found, it will take 10-15 years between the emergence of an idea and the introduction of a drug to the market. This creates priority for the development of neuro-lymphaphotonics based on the development of promising non-pharmacological strategies for managing functions of the meningeal lymphatic vessels (MLVs). MLVs play a crucial role in the removal of toxins and metabolites from brain as well as in regulation of brain homeostasis and its immunity. Since MLVs are located on the brain surface, light penetrating the skull easily reaches MLVs and affects their functions. Therefore, MLVs are an ideal target for photobiomodulation (PBM). The pioneering studies have shown that PBM of MLVs is a promising strategy for the treatment of a wide range of neuropathology, including Alzheimer's or age-related brain diseases, brain tumor, intracranial hemorrhage, brain damages caused by diabetes. It has recently been discovered that sleep enhances the therapeutic effects of PBM and is a "therapeutic window" in overcoming the limitations of PBM in the elderly. Considering that the PBM technologies are non-invasive and safe with commercially viable possibilities (portability and low cost), neuro-lymphaphotonics open up promising prospects for the development of future technologies for the effective therapy of brain diseases.

Rationale: Metabolic remodeling occurs during partial hepatectomy (PHx)-induced liver regeneration. Phospholipid remodeling during this process and its subsequent impact on liver regeneration remain unknown. The remnant liver's ability to defend against injury is also essential for normal liver regeneration, although the underlying mechanisms remain unclear. Methods: Phospholipidomics was performed to describe phospholipid remodeling after 70% PHx. Phosphate cytidylyltransferase 2, ethanolamine (PCYT2) was overexpressed in hepatocytes using adeno-associated virus under the thyroxine-binding globulin promoter. An ex vivo liver perfusion system was used to regulate portal pressure. GalNAc-conjugated PEG-PCL nano-particles (NPs) were developed to deliver the PCYT2 inhibitor, meclizine. Results: We found a significant decrease in a series of phosphatidylethanolamine (PE) levels at 1 day after 70% PHx. PCYT2, an enzyme for PE synthesis, was downregulated by PHx. Higher portal pressure-induced shear stress is an early event after PHx. As a target gene of hepatocyte nuclear factor 4α, PCYT2 levels were decreased by higher portal pressure. Hepatocyte-specific PCYT2 overexpression aggravated liver damage after PHx by increasing reactive oxygen species levels, lipid peroxidation, and mitochondrial fragmentation. We observed higher hepatic PCYT2 levels in middle-aged mice than in young mice. PCYT2 inhibition by meclizine facilitates liver regeneration in middle-aged mice. Meclizine is also a blocker of the histamine H1 receptor, a membrane receptor. Therefore, we used NPs to deliver meclizine into cells to better target PCYT2 and prevent potential side effects. NP-meclizine improved liver regeneration in middle-aged mice, demonstrating higher therapeutic efficacy than carrier-free meclizine. Conclusions: Decreased PCYT2 levels and PE content due to increased portal pressure protect hepatocytes from PHx-induced injury. Inhibiting PCYT2 with NP-meclizine promoted normal liver regeneration in middle-aged mice.

Rationale: Repairing bone defects in osteoporotic patients presents a significant clinical challenge due to inadequate osseointegration, persistent inflammation, and elevated oxidative stress. To overcome these barriers, this study proposes the development of a functionalized 3D-printed titanium alloy porous scaffold capable of sequentially releasing therapeutic agents to modulate the immune environment and enhance bone regeneration. Methods: A thermosensitive collagen hydrogel was integrated with a zeolitic imidazolate framework (ZIF-8) to construct a dual-release platform capable of delivering the immunomodulator 4-octyl itaconate (4-OI) and the osteogenic factor bone morphogenetic protein-9 (BMP-9) in a temporally controlled manner. The hydrogel facilitated early-phase release of 4-OI to inhibit M1 macrophage polarization and mitigate oxidative stress, while ZIF-8 enabled sustained BMP-9 release to induce osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Comprehensive in vitro assays and an osteoporotic rat model were employed to evaluate the scaffold's immunomodulatory properties, osteogenic capacity, and osseointegration performance. Results: The scaffold inhibited pro-inflammatory cytokine expression, attenuated osteoclast activity, and enhanced osteogenic marker levels in vitro. In vivo analysis revealed enhanced bone-implant interface integration and significantly accelerated bone regeneration in osteoporotic defects. Transcriptome analysis revealed suppression of NF-κB and TGF-β signaling, confirming the scaffold's combined immunomodulatory and osteoinductive effects. Conclusions: This ZIF-functionalized hydrogel scaffold with sequential release capability offers a potential strategy for clinical translation in osteoporotic bone defect repair. By orchestrating local immune modulation and promoting sustained osteogenesis, the system offers a clinically relevant approach to enhance osseointegration and facilitate long-term bone repair in osteoporotic conditions.

Background: Reactive astrocytes form a chemical and mechanical glial scar that inhibits neuro-regeneration after stroke. Astrocyte heterogeneity is accompanied by changes in morphology and mechanical properties altering during scar formation after injury. This work aimed to elucidate the relationship between glial scar stiffness and astrocyte subtype transformation. Methods: Astrocyte-specific archaerhodopsin-3 and channelrhodopsin-2 knock-in C57BL/6J mice underwent distal MCAO. Atomic force microscopy, ultrasound elastography and synchrotron radiation were used to determine changes in glial scar stiffness. A proteomic analysis of astrocyte subtypes was performed ex vitro using single-cell laser capture microdissection-MS. Furthermore, optogenetics was employed in vivo to reduce the glial scar stiffness, thereby facilitating neural regeneration following brain injury. Results: Glial scar stiffness systematically increases following stroke and correlates with an increased number of Wnt7b⁺ fibrotic astrocytes. Furthermore, these results indicate that Piezo1 is the key regulator of astrocytic stiffness and anisotropy, which contributes to the glial scar stiffness in the peri-infarct area. The downregulation of Piezo1 expression promotes activation of the Wnt7b-Ca²⁺ nonclassical signaling pathway to modulate cytoskeletal reorganization. Finally, the specific optogenetic inhibition of Ca²⁺ signaling in astrocytes can effectively reduce glial scar stiffness by decreasing the proportion of Wn7b⁺ astrocytes, which further promotes neuro-regeneration and improves the recovery of motor function after ischemic stroke. Conclusions: This study successfully revealed astrocyte subtype transformation as a key determinant of glial scar physical barrier formation after stroke and highlighted Piezo1 as a potential therapeutic target for modulating the mechanical microenvironment post-injury.

Cancer-associated fibroblasts (CAFs) play a crucial role in the tumor microenvironment, where they facilitate tumor progression, angiogenesis, immune evasion, and treatment resistance, highlighting the urgent need for CAF-targeted strategies for high-performance tumor therapy. Recent nanomedicine approaches have shown promise in CAFs targeting in order to achieve precise targeting, spatiotemporal control of drug release, and enhanced drug penetration into dense fibrotic stroma. Accordingly, this review summarizes emerging nanotechnologies that address challenges through the development of functional nanomaterials for CAFs targeting, including polymers, metal and non-metal inorganic nanoparticles (NPs), cell membrane-based NPs, and protein-based NPs. Specifically, various therapeutic approaches such as direct CAFs depletion, signaling pathway modulation in CAFs, and CAFs reprogramming by using these nanomedicines are discussed. Furthermore, potential avenues for future studies, including the development of versatile nanosystems and the exploration of personalized treatment regimens, and challenges of advanced functional nanomaterials are involved as well. We hope that this review will offer new insights into cancer therapy and advance the development of clinically applicable CAF-targeted nanomedicines.

Rationale: Natural killer (NK) cells are emerging as a promising source of immunomodulatory secretomes with regenerative potential. However, heterogeneity in primary NK cell populations limits the reproducibility of NK-derived cell-free therapies. To address this, we developed directly reprogrammed NK (drNK) cells with a stable CD56^brightCD16^bright phenotype and investigated the therapeutic potential of their conditioned medium (drNK-CM) in wound healing, focusing on underlying molecular mechanisms such as chemokine signaling and angiogenesis. Methods: drNK cells were generated by transcription factor-mediated reprogramming (OCT4, SOX2, KLF4, MYC) and characterized via flow cytometry and RNA-seq. The secretome profile of drNK-CM was evaluated using proteomic analysis. Human epidermal keratinocytes (HEKs), dermal fibroblasts (HDFs), and endothelial cells (HUVECs) were treated with drNK-CM to assess proliferation, migration, and extracellular matrix (ECM) remodeling. Chemokine receptor involvement was evaluated using CCR1, CCR3, and CCR5 antagonists. In vivo efficacy was tested in mouse excisional wound models, with histological and immunofluorescence evaluation of angiogenesis, re-epithelialization, and collagen deposition. Results: drNK-CM significantly promoted proliferation and migration of HEKs, HDFs, and HUVECs, accompanied by enhanced expression of Type I/III collagen, VEGF, and MMPs. Transcriptomic profiling revealed that drNKs uniquely upregulated genes associated with ECM remodeling, chemokine signaling (CCL3/4/5), and angiogenesis. Notably, CCR5 inhibition by maraviroc abrogated drNK-CM-induced cell migration and delayed wound closure in vivo, highlighting the central role of the CCL3/4/5-CCR5 axis. Furthermore, drNK-CM activated AKT and ERK pathways and promoted anti-inflammatory macrophage polarization. In vivo application of drNK-CM accelerated wound closure, improved neovascularization, and supported organized tissue regeneration compared to controls. Conclusion: This study demonstrates that drNK-CM enhances wound healing through coordinated actions on epithelial, stromal, and endothelial compartments. The reparative effects are primarily mediated via the CCL3/4/5-CCR5 signaling axis and pro-angiogenic cascades. Given their consistent phenotype and reproducible secretome, drNKs represent a scalable and safe source for cell-free regenerative therapeutics.

Short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, serve as pivotal metabolites within the tumor microenvironment (TME), playing essential roles in modulating tumor progression. Although the biological functions and mechanisms of SCFAs in the TME show some overlap, each SCFA also exerts some distinct regulatory effects on tumors and TME. Notably, even a single SCFA may exhibit pleiotropic effects across different cancer types or under varying conditions within the same malignancy. Consequently, according to the different metabolic microenvironment of patients, precise modulation of SCFA levels could effectively suppress tumor progression. Furthermore, SCFAs have been shown to potentiate the therapeutic efficacy of immunotherapy, radiotherapy, and chemotherapy. This review systematically outlines the sources, biological functions, and mechanisms of different SCFAs in the TME, while exploring potential therapeutic strategies based on SCFA modulation. These insights offer novel perspectives and directions for future research and clinical cancer therapy.

Early detection of metastatic disease improves cancer survival, yet existing modalities are limited in their detection capabilities. We propose that magnetic particle imaging (MPI), an emerging technology, can be used for early detection of primary tumors and metastases. MPI detects minute quantities of magnetic particles that act as "cold tracers" which accumulate in areas of high immune activity. Methods: Pegylated Synomag® nanoparticles were intravenously injected into mouse models of breast cancer bearing primary tumors and spontaneously developed lung metastases. After 72 h, mice were subjected to three-dimensional MPI followed by structural imaging for co-registration. Non-tumor bearing mice served as controls for background signal correction and toxicity analysis. Animals were then sacrificed to collect tumors and organs of interest for two-dimensional MPI scans before fixing them for histopathological evaluation by hematoxylin and Eosin (H&E), Prussian blue, and immunohistochemistry staining. To further substantiate our findings towards clinical translation, tumor phantoms with nanoparticles were evaluated in a newly-built human scale MPI. Results: Pegylated Synomag® nanoparticles showed a strong signal in both in vitro and in vivo models. Multiple macro and micro metastatic sites were identified by MPI and later confirmed by histology. Ex vivo quantitative analysis showed MPI can detect metastasis with high specificity and sensitivity, with positive correlations between tumor burden and macrophage population in the tumor microenvironment. Towards clinical translation, we also demonstrate nanoparticle detection in tumor phantoms using a human-scale MPI. Conclusion: MPI using Pegylated Synomag® nanoparticles can successfully detect primary tumors and micrometastases away from large organs of the reticuloendothelial system. Nanoparticles were found in the tumor microenvironment, associated with stromal and immune cells, especially macrophages. This provides evidence to use MPI for noninvasive detection of highly inflammatory tumors and metastasis, as well as exploring their potential for other inflammatory diseases.

Background: The intranasal (IN) route offers a promising noninvasive strategy for central nervous system drug delivery bypassing the blood-brain barrier and reducing systemic exposure. However, its clinical translation is limited by low delivery efficiency and a lack of regional specificity in the brain. Here, we present the first demonstration of focused ultrasound-mediated intranasal delivery (FUSIN) in a large-animal model to address these limitations. Methods: Pigs were used to develop and characterize IN delivery, evaluate systemic exposure in major organs, and assess the feasibility and safety of FUSIN for delivering a therapeutic antibody, anti-programmed death-ligand 1 antibody (aPD-L1). The IN delivery was performed using a catheter-based approach, and successful delivery was confirmed with gadolinium-based contrast agents in combination with magnetic resonance imaging (MRI). Systemic exposure was assessed following IN administration of fluorescently labeled IRDye 800CW-aPD-L1, and its biodistribution was compared with intravenous (IV) injection of IRDye 700CW-aPD-L1. FUSIN delivery was performed by applying focused ultrasound (FUS) to predefined brain targets following IN administration to enhance local antibody accumulation. Delivery outcomes were assessed by ex vivo fluorescence imaging, followed by immunofluorescence staining, and safety was evaluated using susceptibility-weighted imaging (SWI). Results: IN delivery targeted the olfactory epithelium region and resulted in significant accumulation of 800CW-aPD-L1 in brain regions associated with the olfactory and trigeminal pathways, while markedly reducing off-target deposition in peripheral organs compared to IV administration. The application of FUS significantly increased local antibody accumulation at the targeted sites compared to contralateral non-sonicated controls. Immunofluorescence imaging revealed FUS-enhanced transport of the antibody from perivascular spaces into the brain interstitial space. SWI detected microhemorrhages under the current FUS parameters, highlighting the need for optimization to ensure safety. Conclusion: This study demonstrates the feasibility of FUSIN for noninvasive, region-specific brain drug delivery with minimized systemic exposure in a large-animal model.