Theranostics最新文献

Endometrial regeneration remains a significant clinical challenge for women with intrauterine adhesions (IUAs), thin endometrium, or uterine factor infertility, conditions that severely impair fertility and reproductive outcomes. Traditional hormonal and surgical interventions often fail to restore the structural and functional integrity of damaged endometrial tissue. This review comprehensively examines integrative bioengineering strategies for endometrial regeneration, focusing on the synergistic applications of biomaterials, stem cells, organoids, and organ-on-a-chip technologies. Natural polymers such as collagen, gelatin, alginate, hyaluronic acid, and synthetic polymers including PCL, PLA, PGA, and PLGA have been comprehensively evaluated for their ability to mimic extracellular matrix, support cell proliferation, angiogenesis, and modulate immune responses. The incorporation of mesenchymal stem cells, extracellular vesicles, and growth factors into bioengineered scaffolds, such as hydrogels and nanofiber membranes, enhances regenerative efficacy. Furthermore, emerging platforms, such as endometrial organoids, 3D bioprinting, and organ-on-a-chip systems, offer physiologically relevant models for precision regenerative medicine. Innovations such as AI-assisted monitoring, 4D printing, and advanced drug delivery systems represent transformative approaches to overcome current therapeutic limitations. This review highlights the convergence of materials science, stem cell biology, and microengineering as a foundation for next-generation, personalized therapies aimed at restoring endometrial function and fertility. In addition, the review highlights biomaterial-based strategies as the foundation of endometrial regeneration, by detailing how natural polymers (e.g., collagen, gelatin, alginate, hyaluronic acid) and synthetic polymers (e.g., PCL, PLA, PLGA) support tissue repair structurally and by mediating biological functions. The integration of advanced technologies, such as 4D printing, AI-assisted monitoring, and stem cell-derived extracellular vesicle delivery has emerged as a transformative direction for overcoming current clinical challenges. Collectively, these approaches offer a next-generation therapeutic paradigm for restoring endometrial function and fertility.

Rationale: Gamma-glutamyl transferase (GGT) is overexpressed on cancer cell membranes and has been widely used as a promising target for receptor-mediated therapy. However, its heterogeneous expression limits targeting efficacy. Based on the notation that reactive oxygen species (ROS) upregulate GGT and induce oxidative stress-mediated cancer cell death, we hypothesized that GGT-targeted ROS generation could simultaneously induce cell death and also reprogram tumors to achieve self-boosting targeted therapy. Methods: We developed GLOXmp, a glutamic acid (Glu)-coated oxidative stress nanoamplifier, in which glutathione (GSH)-depleting B2C was loaded in ROS-generating amphiphilic polyCA. GLOXmp was designed to induce oxidative stress, modulate GGT expression, subsequently enhancing tumor targeting both in vitro and in vivo using xenograft mouse models. Results: GLOXmp internalized GGT-overexpressing cancer cells and concurrently generated ROS and depleted intracellular GSH, leading to mitochondrial damage and potent cancer cell death. Importantly, GLOXmp reprogrammed tumor cells to upregulate GGT, leading to the enhancement of receptor-mediated uptake of subsequent doses. In tumor xenograft model, repeated administration of GLOXmp significantly elevated oxidative stress, increased GGT expression, and effectively eradicated tumors without systemic toxicity. Conclusion: GLOXmp specifically targeted GGT-overexpressing cancer cells and effectively suppressed tumor development through oxidative stress amplification. Given a self-reinforcing strategy for targeted cancer therapy through oxidative stress-mediated tumor cell reprogramming, GLOXmp demonstrates represents a promising advancement in precision nanomedicine.

Background: Microthrombi obstructing downstream microcirculation in acute ischemic stroke (AIS) are difficult to treat and visualize with current imaging methods. Methods: To address this need, a novel theranostic agent, IO@PDA@tPA, was developed by combining iron oxide microparticles (IO) coated with polydopamine (PDA) and conjugated with recombinant tissue-type plasminogen activator (r-tPA). The amidolytic and fibrinolytic capacities of r-tPA grafted on IO@PDA were assessed using the spectrofluorometric test, the clot lysis assay, and the whole blood halo assay. IO@PDA@tPA was then tested in vivo in a preclinical ischemic stroke model induced by thrombin injection into the middle cerebral artery in both non-diabetic and diabetic mice. Two doses equivalent to 2.5 and 5 mg/kg r-tPA were tested. The presence of microthrombi was monitored via molecular MRI. A series of T ₂*-weighted sequences for microthrombi imaging and magnetic resonance angiography (MRA) was performed over 45 min. At 24 h, lesion size, vessel patency, and hemorrhagic transformation were assessed with T₂ -weighted imaging, MRA, and T₂ ^* -weighted MRI, respectively. A grip test was performed to assess functional recovery one day before stroke (baseline), and at 24 h and five days after stroke. Additionally, inflammatory processes were evaluated five days post-stroke by flow cytometry in the non-diabetic cohort. Results: This agent exhibited in vitro clot lysis activity. In vivo, administration of IO@PDA@tPA at one-quarter of the standard r-tPA dose enabled both visualization and degradation of microthrombi, as detected by T₂ ^* -weighted MRI. This treatment significantly reduced lesion size and promoted recanalization 24 h after stroke onset. In the hyperglycemic mice cohort, the agent demonstrated efficacy comparable to r-tPA without increasing hemorrhagic risk-a common complication of free r-tPA. Moreover, full functional recovery observed within five days post-stroke. Flow cytometry indicated that IO@PDA@tPA mitigated inflammatory processes. Conclusion: IO@PDA@tPA represents a promising theranostic agent targeting microthrombi in AIS, reducing the required r-tPA dose and limiting associated side effects.

Rationale: Glycosylation of drug delivery vehicles enables selective tumor microenvironment (TME) targeting but is limited by the lack of precise glycan control and unbiased evaluation of in situ targeting. We developed a clickable albumin nanoplatform engineered by distinct glycosylation for selective in vivo cell targeting (CAN-DGIT) with a defined number of sugar moieties and integrated spatial transcriptomics (ST) to map nanoparticle-TME interactions. Methods: Albumin was functionalized with azadibenzocyclooctyne (ADIBO) at a controlled degree of functionalization (DOF), confirmed by MALDI-TOF and UV-vis spectroscopy, followed by conjugation of azide-functionalized mannose, galactose, or glucose via click chemistry. Nanoparticles were labeled with ⁶⁴Cu or fluorescent dyes for PET imaging and ex vivo analysis in healthy and 4T1 tumor-bearing mice. ST based algorithms, spatial gene-image integration (SPADE), cell-type deconvolution (CellDART), and image-based molecular signature analysis (IAMSAM), were used to define TME clusters, associated cell populations, and glycan receptor gene signatures. Clodronate-loaded glycosylated albumins were tested for tumor-associated macrophage (TAM) depletion. Results: Glycosylation type of CAN-DGIT dictated pharmacokinetics and targeting. Mannosylated albumin (Man-Alb) showed rapid hepatic retention via mannose receptors on Kupffer cells and TAMs; galactosylated albumin (Gal-Alb) exhibited rapid hepatobiliary clearance with the highest tumor-to-liver ratio; glucosylated albumin at the C6 position (Glc(6)-Alb) progressively accumulated in tumors, correlating with glucose transporter 1 (GLUT1)-expressing cancer cells. ST confirmed Man-Alb enrichment in extracellular matrix (ECM)/TAM-rich clusters (mannose receptor C-type 1, Mrc1-high) and Gal-/Glc-Alb uptake in glycolytic/hypoxic tumor clusters (Slc2a1-high). Man-Alb-clodronate achieved potent CD206+ TAM depletion without altering drug release kinetics. Conclusions: Precisely tuned glycosylation enables programmable biodistribution and cell-type targeting of albumin nanoparticles in the TME. Integrating PET with ST provides a robust framework for mechanistic mapping of nanomedicine uptake. The CAN-DGIT platform offers a versatile strategy for developing targeted theranostic agents with immunomodulatory potential.

Background: Radiotherapy (RT)-induced antitumor immunity has attracted extensive attention. However, such antitumor immunity often proves inadequate to combat metastatic and recurrent tumors in clinical practice. While hypoxia severely limits the initiation of adequate systemic antitumor immune responses, the strength of such responses is further compromised by the blockage of effector T cells, ultimately undermining the ability of RT to elicit a robust abscopal effect and durable immune memory. Methods: Hence, a limitation-circumventing strength-capitalizing hydrogel (UP) is developed to increase the efficacy of RT for a robust abscopal effect and durable antitumor immunity to cope with metastatic and recurrent tumors. Results: With single-administration and radiation treatments, UP efficiently generates oxygen in situ to circumvent the limitation of RT hypoxia. After such limitations are overcome, the tumor-killing capacity of RT is significantly promoted, resulting in strong antitumor immune responses. Moreover, UP further inhibits immune checkpoints to reinvigorate effector T cells, capitalizing on the strength of RT-induced antitumor immune responses. With such strength-capitalization, RT-induced transient immune responses are amplified to systemic immunity, triggering a robust abscopal effect to eliminate distant metastasis and establishing durable immune memory against recurrence. Conclusions: Consequently, UP potentiates the antitumor immunity of RT through circumventing the hypoxia barrier and capitalizing on immune activation. Our study provides new insights into RT enhancement.

Targeting the dysregulation of essential metal homeostasis represents a rapidly evolving frontier in cancer immunotherapy. The tumor microenvironment (TME) is a complex immunosuppressive ecosystem comprising tumor cells, immune cells, stromal components, extracellular matrix, and diverse cytokines/chemokines, characterized by hypoxia, acidosis, elevated redox stress, and metabolic dysregulation that drive tumor progression and immunotherapy resistance. Crucially, dysregulated homeostasis of essential metals (e.g., Cu, Fe, Zn, Mg, Mn, Ca, Cr, Na, K) pervades the TME, directly promoting tumorigenesis through oncogenic pathway activation and aberrant energy metabolism while facilitating immune evasion, amplifying immunosuppression, and undermining cancer immunotherapies. In response, recent strategies have focused on leveraging metalloimmunology to reprogram the TME via: (1) activation of innate/adaptive immunity, (2) disruption of tumor metabolism, (3) induction of programmed cell death, and (4) triggering of immunogenic cell death (ICD). These approaches synergize with existing immunotherapies to enhance efficacy, aided by nanotechnology-enabled precision delivery of metal-based agents. In conclusion, by mastering the intricate interplay between metal ions and the immunosuppressive TME, these strategies hold immense potential to remodel the TME, reinvigorate anti-tumor immunity, and ultimately enhance the efficacy of next-generation cancer immunotherapies. This review presents metalloimmunology as an integrative paradigm connecting metal biology, tumor immunology, and nanotechnology, providing a transformative outlook for immunotherapy.

Rationale: Endothelial cell senescence leads to endothelial dysfunction, thereby promoting the progression of atherosclerosis. Super-enhancers are crucial epigenetic cis-regulatory elements whose extensive reprogramming drives aberrant transcription in human diseases. However, the underlying mechanisms by which super-enhancers regulate endothelial cell senescence remain unclear. This study reveals the effect of liquid-liquid phase separation (LLPS) mediated by super-enhancer-driven core transcription factor FOXP1 on endothelial cell senescence. Methods: The landscape of super-enhancers, chromatin accessibility, and transcriptome profiling were characterized during endothelial cell senescence by conducting CUT&Tag-seq with antibodies against H3K27ac, H3K4me1, and H3K4me3, along with assays for ATAC-seq and RNA-seq. The Coltron algorithm was used to identify core transcription factors in the process of endothelial cell senescence. Fluorescence recovery after photobleaching (FRAP), dCas9-KRAB CRISPRi, and the Optodroplet assay were utilized to confirm the phase separation properties of FOXP1. Functional experiments were employed to elucidate the effect of FOXP1 on endothelial cell senescence through LLPS. Results: Senescent endothelial cells undergo significant changes in their epigenome. FOXP1 is identified as a core transcription factor, driven by super-enhancers, which delays endothelial cell senescence and inhibits atherosclerosis. Moreover, FOXP1 undergoes LLPS, which the 19 phase-forming amino acids within the intrinsically disordered region of FOXP1 are capable of maintaining its ability to delay endothelial cell senescence. Mechanistically, FOXP1 activates the target gene SESN3 and inhibits the mTORC1 signaling pathway through phase separation, a key event in delaying endothelial cell senescence. The clinical evidences support the potential role of FOXP1 and SESN3 as protective factors against atherosclerosis. Conclusion: FOXP1 undergoes phase separation at its super-enhancer, recruiting transcription coactivators to form condensates. These condensates, in turn, facilitate binding with the SESN3 promoter and inhibit the mTORC1 signaling pathway, thereby delaying endothelial cell senescence.

Rationale: Transmembrane 4 superfamily member 4 (TM4SF4) has been identified as a key regulator of epithelial-mesenchymal transition (EMT)-associated stemness in non-small cell lung cancer (NSCLC) cells through autocrine signaling involving insulin-like growth factor 1 (IGF1) and osteopontin (OPN). Given its pivotal role in tumor progression and therapy resistance, TM4SF4 represents a promising therapeutic target. Methods: To develop a therapeutic antibody against TM4SF4, we generated anti-TM4SF4 monoclonal antibodies in mice by targeting the large extracellular loop (LEL) of human TM4SF4 using a 15-mer peptide, hTM4SF4 (T126-E140). Among the generated clones, the 2B7 antibody exhibited high specificity and reactivity to TM4SF4. Mechanistic studies were conducted to evaluate the effects of 2B7 on key signaling pathways, EMT-associated stemness, immune checkpoint ligand (ICL) expression, and immune responses. To facilitate clinical translation, 2B7 was humanized, generating the Hz2B7-1.1 antibody, which underwent affinity maturation to select the lead candidate, Hz2B7-1.2. Functional assays, including antibody-dependent cellular cytotoxicity (ADCC) and preclinical evaluations in xenograft models, were performed to assess its therapeutic potential. Results: The 2B7 antibody demonstrated significant antitumor efficacy in both A549 xenograft and patient-derived xenograft (PDX) models. Mechanistically, 2B7 inhibited key signaling pathways, including PI3K/AKT/GSK3β/β-catenin and JAK2/STAT3, leading to a reduction in EMT-associated stemness and therapy resistance. Additionally, 2B7 downregulated the expression of ICLs, such as PD-L1 and B7-H4, promoting T-cell activation and mitigating immune evasion. Furthermore, 2B7 reduced the secretion of exosomal ICLs by tumor cells and enhanced antitumor immune responses. The humanized antibody Hz2B7-1.2 retained binding properties and antitumor activity comparable to the parental 2B7 antibody and effectively induced ADCC as an IgG1-type antibody. Conclusions: The humanized anti-TM4SF4 antibody, Hz2B7-1.2, exhibits strong antitumor activity through multiple mechanisms, including inhibition of oncogenic signaling pathways, reduction of EMT-associated stemness, and modulation of immune responses. These findings support Hz2B7-1.2 as a promising therapeutic candidate for TM4SF4-positive cancers, warranting further clinical investigation.

The role of bacteria in tumor development has been increasingly recognized through advances in sequencing technologies, revealing their influence on the tumor microenvironment and immune system. Live bacterial therapy, known for its unique ability to target tumors, colonize cancerous tissues, and activate immune responses, is emerging as a novel approach to cancer treatment. To enhance the therapeutic efficacy and safety of this strategy, various engineering techniques have been developed to modify bacteria, enabling the creation of advanced bacteria-based drug delivery systems. Living probiotics can selectively colonize the tumor microenvironment, where they interact with immune cells to enhance antitumor responses. This review provides an overview of the complex relationship between bacteria and tumors and discusses engineering methods for bacterial modification, including physicochemical approaches and synthetic biology. It further highlights the applications of these strategies in enhancing cancer therapies. Finally, it examines the future opportunities for engineered bacteria in cancer therapy, focusing on the potential of combination therapies, personalized medicine, and the role of the microbiome in enhancing therapeutic outcomes. With ongoing advancements, engineered bacteria hold great promise for improving the efficacy and safety of cancer treatments, offering a new frontier in oncology.

Rationale: Sigma-1 receptor (sigma-1R) is a promising biomarker and therapeutic target for ischemic stroke. However, the real-time changes in the expression of sigma-1R post-stroke have not been elucidated. (R)-1-(4-[¹⁸F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine ((R)-[¹⁸F]FBFP) has emerged as a novel radiotracer targeting sigma-1R. This study aimed to use (R)-[¹⁸F]FBFP PET imaging for the investigation of spatiotemporal alterations in sigma-1R expression in the rat brain following stroke and treatment, and to explore the correlation between the imaging findings and neurological outcomes. Methods: Sigma-1R levels were evaluated on days 1, 3, 7, 14, 21, and 28 after middle cerebral artery occlusion (MCAO) using (R)-[¹⁸F]FBFP PET/CT imaging. Ex vivo autoradiography and immunofluorescence (IF) staining were performed to corroborate the findings from PET/CT imaging. The cellular localization of sigma-1R during stroke progression was identified by co-labeling sigma-1R with neurons (NeuN), astrocytes (GFAP), and microglia (Iba1). Behavioral tests were conducted on MCAO rats at corresponding time points, and the correlation between PET signals and neurological outcomes was analyzed. The MCAO rats were then treated with recombinant tissue-type plasminogen activator (rtPA), and the therapeutic response was evaluated with (R)-[¹⁸F]FBFP to elucidate the impact of treatment on PET imaging. Results: Compared with the sham group, the ipsilateral-to-contralateral hemisphere uptake ratio of (R)-[¹⁸F]FBFP of the MCAO group significantly decreased in the acute phase (days 1 and 3), increased in the subacute phase (days 7 and 14), and then gradually declined in the chronic phase (days 21 and 28). The PET imaging findings were in agreement with the ex vivo autoradiography and IF staining. Changes in sigma-1R levels in ischemic lesions were influenced by the initial neuronal loss and the later accumulation of glial cells. Furthermore, there was a significant correlation between the uptake of (R)-[¹⁸F]FBFP and the neurological outcomes during stroke recovery. After rtPA treatment, the (R)-[¹⁸F]FBFP uptake in the affected hemisphere gradually returned to levels comparable to the contralateral hemisphere. Conclusions: (R)-[¹⁸F]FBFP PET imaging effectively visualized and accurately quantified the spatiotemporal alterations of sigma-1R in the rat brain during ischemic stroke progression. The (R)-[¹⁸F]FBFP uptake correlated with the neurological outcomes during stroke recovery, and (R)-[¹⁸F]FBFP PET imaging could be a valuable tool for predicting post-stroke recovery and evaluating the efficacy of rtPA treatment.