搜索结果：Journal of nanobiotechnology

Neurological disorders refer to a diverse group of conditions that affect the brain, peripheral nerves, and spinal cord and impair socioemotional, cognitive, motor, and sensory functions. Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are some of the well-known neurodegenerative diseases that affect millions of people worldwide. Despite the advanced technologies and nano-drug delivery systems, the success rate of developing drugs for neurological disorders is significantly low. Among several constraints, including gastrointestinal irritation, rapid metabolism, and low stability, the blood-brain barrier (BBB) emerges as one of the key challenges in the development and application of drugs against neurological disorders. These challenges necessitate innovative approaches to develop cost-effective therapeutic strategies. Drug repurposing, the discovery of new therapeutic benefits of existing drugs, is a promising drug discovery approach for discovering potential treatment options for complex neurological disorders. This review aims to explore the advanced and significant progress in drug repurposing for major neurological disorders, including MS, AD, PD, ALS, HD, stroke, and neuropsychiatric conditions. It places an explicit emphasis on discussing the potential role of artificial intelligence (AI)-assisted drug repurposing and understanding of the biological mechanisms in discovering new drugs for these neurological conditions. This also examines current challenges in drug repurposing and provides a critical review of the available opportunities and limitations in AI-assisted drug repurposing.

Radiotherapy remains a cornerstone in the clinical management of malignancies, leveraging DNA damage and oxidative stress to eradicate tumor cells. Nonetheless, the emergence of intrinsic and acquired radioresistance significantly compromises its therapeutic efficacy. While nanomedicine has substantially advanced radiosensitization strategies, the existing literature has largely focused on physical dose enhancement or conventional apoptosis, and the systematic reprogramming of diverse cell death modes beyond conventional apoptosis in the radiotherapy context has received less systematic attention. The present review provides a cross‑pathway synthesis of how engineered nanomaterials redirect tumor cell fate beyond apoptosis to achieve next‑generation radiosensitization, while also identifying the specific limitations and knowledge gaps that currently impede progress in this rapidly evolving field. We first delineate the hierarchical sensitization mechanisms, beginning with physical energy deposition via high-Z elements, followed by chemical amplification of reactive oxygen species through nanozyme catalysis, and biological intervention in the "6R" principles of radiobiology. Crucially, we evaluate the potential capacity of advanced nanomaterials to bypass conventional apoptotic resistance by triggering ferroptosis, pyroptosis, cuproptosis, disulfidptosis, and other emerging programmed death pathways, with a focus on the current evidence base and remaining preclinical and translational challenges. Beyond localized cytotoxicity, we highlight the mechanistic potential of nanomedicine to induce immunogenic cell death and activate the cGAS-STING pathway, suggesting a possible framework for transforming RT into an "in situ vaccine" that could reshape the immunosuppressive TME. Furthermore, we discuss the clinical translation of landmark nano-radiosensitizers, such as NBTXR3 and AGuIX, while critically addressing fundamental bottlenecks in targeting efficiency, biodistribution, and biosafety. By synthesizing current trends and future perspectives, this review contributes a strategic roadmap for advancing the design of next-generation, intelligent nanoplatforms toward more precise and systemic radiosensitization.

Chronic diabetic wounds remain a formidable clinical challenge due to a self-sustaining immunometabolic dysfunction. The hyperglycemic and pro-oxidative microenvironment locks infiltrating macrophages in a glycolysis-dependent pro-inflammatory state, actively suppressing the phenotypic switch to pro-reparative M2 polarization and severely impairing angiogenesis. Current single-target interventions fail to disrupt this vicious inflammatory-metabolic cycle, underscoring an urgent need for strategies capable of spatiotemporally resetting local immune homeostasis. In this study, the pro-reparative capacity of ADSCs-EVs and UCMSCs-EVs was systematically compared through a panel of in vitro functional assays (proliferation, migration, tube formation, and macrophage polarization) and a diabetic mouse wound model. Small RNA sequencing was employed to identify a key effector miRNA enriched in UCMSCs-EVs, and its target regulatory mechanism was validated through miRNA mimic transfection combined with HDDC3 overexpression rescue experiments. Meanwhile, a glucose/ROS dual-responsive injectable hydrogel (DCH) was constructed from oxidized dextran, carboxymethyl chitosan, and phenylboronic acid-modified hyaluronic acid via physical mixing and dynamic double crosslinking through Schiff-base and boronate ester bonds, enabling the pathology-triggered, on-demand release of EVs. Comparative bioactivity profiling revealed that extracellular vesicles derived from umbilical cord mesenchymal stem cells (UCMSCs-EVs) exhibited greater capacity than adipose-derived EVs to drive macrophage M2 polarization and metabolic reprogramming. Mechanistic dissection identified miR-423-5p as a highly enriched cargo within UCMSCs-EVs. This microRNA directly targeted and suppressed HDDC3 expression, thereby modulating the AMPK/mTOR signaling axis to enforce a metabolic shift from glycolysis toward fatty acid oxidation and establish a stable pro-repair phenotype. To address the poor retention and rapid clearance of free EVs within the hostile wound bed, an injectable dual-network hydrogel was engineered, integrating dynamic boronate ester and Schiff-base crosslinks. This smart platform maintained structural integrity under physiological conditions yet underwent selective dissociation exclusively in response to the elevated glucose and reactive oxygen species (ROS) levels characteristic of diabetic wounds. This pathology-triggered degradation facilitated on-demand, sustained release of UCMSCs-EVs while concurrently scavenging local ROS. The synergistic coupling of this microenvironment-responsive delivery with miR-423-5p-encoded immunometabolic regulation effectively resolved chronic inflammation and accelerated granulation tissue formation. This study establishes a translatable framework for precision regenerative medicine by integrating stimuli-responsive biomaterial engineering with the intrinsic regulatory circuitry of stem cell-derived EVs, effectively overcoming the immunometabolic barriers inherent to diabetic tissue repair.

Adenomyosis (AM) is frequently associated with compromised embryo implantation. The leukemia inhibitory factor (LIF)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is crucial for endometrial receptivity; however, its mechanistic role in AM-related implantation failure remains insufficiently elucidated. This study aimed to investigate the inactivation mechanism of the LIF/STAT3 pathway in AM and to evaluate a novel nanotherapeutic strategy for restoring implantation capacity. Clinical endometrial samples from AM patients and controls were analyzed. A three-dimensional (3D) co-culture system simulating the endometrial microenvironment was established. Interventions were performed using a tofacitinib-loaded biomimetic nanogel (Tofa-NG). Comprehensive analyses included bulk RNA Sequencing (RNA-seq), immunohistochemistry (IHC), RT-qPCR, proteomics, inflammatory cytokine profiling, and metabolomics to dissect the pathological links. The LIF/STAT3 signaling pathway was significantly downregulated in the endometrium of AM patients, correlating directly with implantation failure. Pathologically elevated inflammatory cytokines suppressed LIF expression via NF-κB pathway activation, exacerbating the inflammatory microenvironment. Metabolomic profiling revealed a strong association between LIF/STAT3 pathway inactivation and aberrant cellular energy metabolism. The engineered Tofa-NG facilitated targeted drug delivery, effectively mitigated local inflammation, and successfully reactivated the LIF/STAT3 pathway. Consequently, this intervention significantly improved the embryo implantation success rate in the experimental model. This study identifies the inactivation of the LIF/STAT3 pathway as a central mechanism underlying embryo implantation defects in AM, intricately linked to chronic inflammation and metabolic dysregulation. The Tofa-NG strategy demonstrates promising therapeutic potential by rectifying the signaling deficit and ameliorating the endometrial microenvironment. These findings provide a novel theoretical foundation for developing targeted, personalized treatments for infertility associated with AM.

Nanoparticle mechanical properties, as critical factors in tumor targeting drug delivery, have recently been revealed to regulate cellular biological functions. While macroscopic mechanical stimuli are demonstrated to reprogram tumor-associated macrophages (TAMs), it is unclear how TAMs respond to microscopic stimuli from nanoparticles. Herein, we demonstrated that the stiff 15%NGs presented stronger interactions with integrin than the soft 2%NGs, promoting the polymerization of actin and the activation of yes-associated protein 1. Therefore, the pro-inflammatory phenotype of TAMs was enhanced and the secretion of tumor necrosis factor α was increased. In synergy with high liver enrichment, 15%NGs exhibited superior tumor suppression by reprogramming TAMs in orthotopic liver tumors. Crucially, the pro-inflammatory phenotype of macrophages reprogrammed by 15%NGs significantly induced the apoptosis of tumor cells in ex vivo hepatocellular carcinoma tissues from patients. This study proposes a mechanical signaling pathway to reprogram TAMs by manipulating nanogel stiffness and provides new insights for rational design of cancer nanomedicines.

Activating the stimulator of interferon genes (STING) pathway is a potent strategy for promoting tumor vascular normalization and enhancing cancer immunotherapy. However, the poor metabolic stability of classical STING agonists limits their clinical translation. Herein, we engineered a self-assembled Au-Se nanoplatform (AAC) for the co-delivery of the STING agonist cyclic 2',3'-GMP-AMP (cGAMP) and the hypoxia-inducible factor-1α (HIF-1α) inhibitor acriflavine (Acf). Upon cellular internalization, the weakly acidic tumor microenvironment (TME) triggers the synchronized release of cGAMP and Acf agents. Next, cGAMP activates the STING pathway to induce type I interferon (IFN-I) production, while Acf disrupts HIF-1α/β dimerization. The activation of STING signal pathway and the inhibition of HIF-1α/β expression synergistically suppress the expression of VEGFA and remodels the TME into an immune-permissive milieu, which promotes vascular normalization and elicits tumor immune response. Combined with the photothermal therapy (PTT) of Au nanorods, AAC induces robust immunogenic cell death (ICD), facilitates dendritic cell (DC) maturation, and enhances cytotoxic T lymphocytes (CTLs) infiltration. In murine breast cancer models, AAC effectively suppressed both primary and distant tumors, highlighting its potential as a versatile nanotherapeutic platform for synergistic photothermal enhanced immunotherapy.

Pulmonary edema, a life-threatening condition in acute lung injury/acute respiratory distress syndrome (ALI/ARDS), is driven by dysregulated inflammation, barrier disruption, and alveolar fluid accumulation. Effective therapies that simultaneously target these multiple pathological processes with high lung specificity are urgently needed. We engineered carrier-free, self-assembled nanoparticles from the natural products magnolol (Mag) and atractylenolide I (ATI) at an optimal 4:1 molar ratio. The Mag-ATI nanoparticles (MA NPs) exhibited an average hydrodynamic diameter of approximately 220.2 nm, excellent colloidal stability, and a pH-responsive release profile favorable for the acidic pulmonary microenvironment. The drug loading was 81.7 ± 0.356% for Mag and 18.2 ± 0.129% for ATI, encapsulation efficiency exceeded 97% for both. In a murine lipopolysaccharide (LPS)-induced ALI model, MA NPs potently ameliorated pulmonary edema, outperforming individual drugs or their physical mixture. Biodistribution studies confirmed the MA NPs' efficient lung accumulation, with a fluorescence intensity 3.6-5.9 times higher than in other organs, and specific targeting to alveolar epithelial cells. Mechanistically, Mag inhibited TRPV4-mediated Ca2+ influx, thereby suppressing the downstream cAMP/AQP5 axis to limit water permeability and restore alveolar fluid balance. Mag and ATI attenuated inflammatory signaling via the protein kinase B (AKT)/nuclear factor kappa B (NF‑κB) pathway. Furthermore, Mag and ATI preserved epithelial barrier integrity by stabilizing tight junction proteins. These multi-modal mechanisms were systematically validated both in vitro and in vivo. Importantly, MA NPs demonstrated a favorable safety profile with no significant systemic toxicity. This study presents a novel, carrier-free nanotherapeutic platform that integrates the efficacy-enhancing rationale of traditional herbal medicine with advanced nanoassembly. By enabling coordinated modulation of inflammation, barrier function, and fluid homeostasis, MA NPs offer a potent, targeted, and translational strategy for the treatment of ALI/ARDS.

Osteosarcoma is a highly malignant and metastasis-prone bone tumor, and current treatment options remain unsatisfactory, underscoring the urgent need for new targeted strategies. Induction of cellular senescence represents a promising non-apoptotic antitumor mechanism. Although CK1α is considered to have tumor-suppressive potential, its underlying mechanism and the limited bioavailability of its specific activator pyrvinium pamoate (PP) have hindered clinical translation. Here, we developed a pH-responsive biomineralization-induced peptide self-assembly nanodelivery system (NP@PP) to improve the druggability of PP. Through in vitro and in vivo experiments combined with transcriptomic sequencing, co-immunoprecipitation, and Western blot analysis, we found that PP released from NP@PP efficiently activated CK1α and specifically promoted the ubiquitin-dependent degradation of CBX4. The loss of CBX4 further suppressed YAP1 SUMOylation and blocked its nuclear translocation, thereby activating p16INK4a and p21Cip1 expression, inducing osteosarcoma cell senescence, and inhibiting proliferation and metastasis. In mouse models, NP@PP markedly suppressed xenograft growth and lung metastasis, prolonged survival, and showed no obvious toxicity. These findings reveal a critical role of the CK1α-CBX4-YAP1 signaling axis in senescence-based osteosarcoma therapy and provide a theoretical and practical basis for the development of new nanomedicines.

Cataract is among the leading cause of vision impairment worldwide and it is essential to uncover molecule-level characteristics of different cataract subtypes for personalized treatment. Compared to existing diagnostic techniques, surface-enhanced Raman spectroscopy (SERS) shows advantages in sensitive molecular fingerprinting, tractability and compactness, making it highly suitable for clinical adoption. To further address the current lack of SERS-based techniques for cataract subtyping, this work presented an integrated methodology for robust and interpretable metabolic profiling of aqueous humor. A two-step sample pretreatment protocol has been therein developed to efficiently extract metabolites while ensuring compatibility with subsequent SERS detection. SERSome strategy was employed to enable rapid and robust metabolic profiling. Molecule-level SERSome interpretation was achieved by matching its positive intra-correlation network with metabolites' SERS barcode. Multiple analytical methods including statistical comparison, interpretable machine learning, and association analysis have been leveraged, evidencing key metabolite biomarkers such as ergothioneine, hypoxanthine and uric acid associated with cataract subtyping and diabetic retinopathy. In a word, this study has not only established a systematic methodology for metabolic analysis of aqueous humor but also provided a usable tool for both fundamental research and clinical applications in different diseases with high rapidness, cost efficiency and scalability.

Navitoclax (ABT-263) exhibits strong cytotoxic effects against hepatocellular carcinoma cells in vitro; however, its therapeutic efficacy in vivo is limited by insufficient local drug accumulation and compensatory upregulation of the anti-apoptotic protein myeloid cell leukemia-1 during long-term treatment. In addition, effective immune activation in hepatocellular carcinoma remains challenging due to the immune-privileged hepatic microenvironment. This study aimed to overcome these limitations through a tumor-targeted nanotherapeutic strategy. Dual pH-responsive copolymeric nanoparticles modified with folic acid and co-loaded with navitoclax and indocyanine green (FPNAI) were developed. FPNAI preferentially accumulated at hepatocellular carcinoma sites through folate receptor-mediated targeting and released navitoclax in response to the acidic tumor microenvironment, thereby inducing mitochondria-mediated apoptosis. Upon near-infrared irradiation, indocyanine green generated excessive reactive oxygen species, leading to downregulation of myeloid cell leukemia-1 and further enhancement of apoptotic signaling. The combined effects of navitoclax and reactive oxygen species synergistically promoted tumor cell apoptosis. Moreover, apoptosis induced by FPNAI triggered immunogenic cell death, characterized by dendritic cell maturation and activation of cytotoxic CD8⁺ T cells. In vivo studies demonstrated that FPNAI with near-infrared irradiation achieved significantly improved antitumor efficacy compared with navitoclax monotherapy, while maintaining favorable tumor-targeting capability and biosafety. This study demonstrates that FPNAI enhances the antitumor activity of navitoclax by integrating targeted drug delivery, reactive oxygen species-mediated mitochondrial apoptosis, and immunogenic cell death induction. The proposed nanotherapeutic platform represents a promising approach for improving hepatocellular carcinoma treatment outcomes.

The therapeutic efficacy for cervical cancer treatment is limited by insufficient drug accumulation and penetration due to physiological barriers such as mucin-rich environments after systemic administration. Thus, developing a local drug delivery system is essential to overcome these hindrances. Active transcytosis of cancer nanomedicines holds great promise for enhancing tumor extravasation, infiltration, and antitumor activity. Herein, polyzwitterionic OPDEA-PCL was developed to encapsulate paclitaxel (PTX) into micelles, serving as an intravaginal therapy for orthotopic cervical cancer. The OPDEA-PCL/PTX micelles efficiently penetrated mucus and exhibited strong resistance to mucin fouling, thereby facilitating rapid transcytosis into tumors. Furthermore, OPDEA-PCL/PTX micelles colocalized with the mitochondria of tumor cells, reversing PTX resistance. In the orthotopic cervical tumor model, the inhibition rate of OPDEA-PCL/PTX micelles was 90.0%, more than 2-fold higher than that of free PTX. In the subcutaneous cervical cancer model which is resistant to PTX. Intravenous administration of OPDEA-PCL/PTX micelles significantly overcame PTX resistance, achieving a tumor inhibition rate of 95.2%, and extending the median survival time by more than 2-fold compared to free PTX and PEG-PCL/PTX treated groups. In summary, this approach holds great promise as a potent localized nanomedicine for cervical cancer treatment with minimal side effects.

Aberrant proximal biomolecular complexes are critical disease biomarkers. The precise in situ imaging of these complexes is essential for deciphering disease pathogenesis and precision diagnostics. However, current in situ analysis technologies are often constrained by limited resolution, diffusion-mediated false positives, or the requirements for rigid conjugation between recognition and amplification moieties, which hampers versatility and multiplexing. Here, we introduce Proximity Anchored Modules Assembly (PAMA), a versatile and multiplexed imaging strategy with a "plug-and-play" architecture. By decoupling target recognition from signal amplification via programmable DNA tracks synthesized by Primer Exchange Reaction (PER), PAMA triggers a polymerase-driven extension exclusively upon dual-recognition events. This mechanism ensures precise proximity-dependent activation, showing a specific signal response to homologous and heterologous targets. We further validated PAMA as a versatile platform for detection of proximal biomarkers by visualizing HER2 receptor dimerization patterns in breast cancer cells and precise discrimination of BCR-ABLP210 fusion gene isoforms in clinical chronic myeloid leukemia (CML) samples. PAMA bridges molecular precision with spatial context through a rapid (approximately 2.5 h) and highly sensitive in situ profiling workflow. Ultimately, PAMA establishes a versatile, modular framework for the precise imaging of diagnostic biomolecular complexes, promising to accelerate both biological discovery and precision clinical diagnostics.

In vivo fluorescent in situ visualization of viral infection dynamics is crucial for elucidating the mechanisms of viral pathogenesis. However, current approaches lack sufficient specificity and sensitivity for spatiotemporal monitoring of viral infection in vivo. Here, we proposed virosome-masked ratiometric nanoprobes (VMR-NPs) integrated with dual-stimuli-responsive near-infrared (NIR) Förster resonance energy transfer (FRET) reporters that specifically recognize influenza A virus (IAV) viral RNA (vRNA) and apurinic/apyrimidinic endonuclease 1 (APE1). Surface hemagglutinin (HA) envelope protein of IAV virosome endows VMR-NPs with enhanced host-cell association and IAV-like intracellular trafficking behavior. Following internalization, vRNA recognition together with APE1-assisted signal amplification modulates the ratiometric fluorescence output of VMR-NPs, enabling sensitive detection of infection-associated signal changes in vitro and in vivo. This study establishes an IAV virosome-masked sensing platform for imaging infection-associated IAV burden and provides a useful tool for studying virus-related biological processes.

Intervertebral disc degeneration (IVDD), primarily driven by oxidative stress and inflammation, significantly impacts patient quality of life. Current therapies lack efficacy, highlighting the need for novel treatment strategies. This study investigates the protective effect of antioxidant hydrogel microspheres containing black phosphorus (BP) nanosheets and extracellular vesicles (EVs), fabricated using a microfluidic technology-based delivery system, designated as EVs@BPMS. In vitro analyses of EVs@BPMS revealed that BP nanosheets enhanced the antioxidant capacity of the hydrogel microspheres. The EVs@BPMS system functioned through the sustained release of extracellular vesicles. These vesicles collectively mitigated oxidative damage by scavenging reactive oxygen species (ROS), reducing oxidative stress, suppressing cellular senescence, and ultimately restoring extracellular matrix homeostasis in nucleus pulposus cells. Transcriptomic analysis further elucidated that the microspheres inhibited inflammatory responses via the IL-17-ferroptosis pathway, providing a theoretical basis for the development of targeted therapeutic interventions. In vivo studies confirmed the protective efficacy of EVs@BPMS in a rat model of IVDD, demonstrating substantial attenuation of disc degeneration. The findings underscored the innovative capacity of antioxidant hydrogel microspheres in regulating oxidative stress and maintaining cellular homeostasis. Moreover, they highlighted the potential of these microspheres for clinical application in degenerative disc disease.

The effective treatment of bacterial infections requires rapid and selective enrichment of antibacterial agents on bacterial surfaces within infectious microenvironments. Transition metal ion-based antibacterial agents show broad-spectrum bactericidal activity, but they usually rely on passive diffusion and stochastic bacterial contact, limiting their ability to establish sufficient local doses within short treatment windows. Herein, an M13 phage-mediated targeting strategy was developed for the rapid enrichment and delivery of copper ion-protocatechuic acid nanoparticles (CP NPs). Through phage display, an M13 phage targeting methicillin-resistant Staphylococcus aureus (MRSA-targeting phage, MTP) and an M13 phage targeting Pseudomonas aeruginosa (P. aeruginosa-targeting phage, PTP) were identified. MTP and PTP retained the typical filamentous morphology of M13 phage and selectively adhered to corresponding bacteria within 1 min. Protocatechuic acid (PCA) was then used as a polyphenolic bridge for phage-surface adhesion and Cu2+ coordination, yielding CP@MTP and CP@PTP, which integrate bacterial recognition, metal-polyphenol assembly, and copper-based antibacterial activity into filamentous delivery scaffolds. After only 10 min of bacterial exposure, CP@MTP selectively reduced MRSA by 3 log, while CP@PTP reduced P. aeruginosa by 1.7 log, likely owing to rapid phage-mediated CP NP enrichment on bacterial surfaces. Transcriptomic analysis further revealed bacterial stress responses induced by targeted copper delivery. In zebrafish larval tail-fin infection models, CP@MTP and CP@PTP effectively eradicated corresponding bacteria and reduced neutrophil recruitment. In a murine P. aeruginosa pneumonia model, CP@PTP prolonged lung retention, reduced pulmonary bacterial burden, and alleviated inflammatory lung injury. This study establishes targeted M13 phages as spatial regulators for rapid and precision antibacterial therapy.

This study aimed to elucidate the biological mechanisms underlying the therapeutic effects of targeted alpha therapy (TAT) using a novel 211At-labeled single-domain antibody drug ([211At]At-AuNP-sdAb). By integrating transcriptomic and metabolomic analyses, we sought to characterize the coordinated gene-metabolite responses induced by α-particle irradiation in melanoma models. B16F10 melanoma cells and tumor-bearing mice were treated with [211At]At-AuNP-sdAb. RNA sequencing and untargeted LC-MS metabolomics were performed to identify differentially expressed genes and metabolites. Functional enrichment, OPLS-DA modeling, ROC curve analysis, and O2PLS-based multi-omics integration were used to explore the molecular networks and candidate indicators. [211At]At-AuNP-sdAb treatment significantly altered the transcription of 777 genes, revealing multi-dimensional cellular stress responses encompassing coordinated nuclear-cytoplasmic perturbations alongside downstream alterations in the mitochondrial respirasome and endoplasmic reticulum homeostasis. Untargeted metabolomic profiling revealed extensive metabolic reprogramming across amino acid, nucleotide, and lipid pathways, identifying key potential candidate indicators such as L-dihydroorotate, and Betaine. Furthermore, O2PLS integration successfully decoded robust multi-system covariance networks, wherein candidate distal metabolic nodes like glucosamine-6-phosphate demonstrated strong correlations with gene clusters regulating microenvironment remodeling. [211At]At-AuNP-sdAb induces multi-dimensional cellular stress and extensive metabolic reprogramming characterized by concurrent genomic damage, subcellular organelle perturbations, and microenvironmental remodeling. The decoded multi-omics covariance networks and specific candidate indicators provide a comprehensive molecular landscape of α-particle-induced biological responses, offering valuable candidate frameworks for monitoring and evaluating TAT therapeutic outcomes.

Androgenetic Alopecia (AGA) is a chronic disease characterized by follicular degenerative changes and the continuous deterioration of the follicular microenvironment. Excessive accumulation of reactive oxygen species (ROS) and insufficient local microcirculation are both critical factors contributing to the onset and progression of this disease. However, existing clinical treatment approaches are mostly confined to single-target interventions for AGA. Herein, a multifunctional hydrogel system that integrates multi-active nanozymes with melanin nano photothermal agents was designed for efficient multimodal synergistic treatment of AGA. Owing to the existence of dynamic covalent bonds, such multifunctional hydrogel exhibits favorable injectability and tissue adhesion capability, facilitating the precise and sustained release of nanodrugs. Among them, multi-active nanozymes can mimic the activities of superoxide dismutase (SOD) and catalase (CAT), enabling efficient cascade clearance of reactive oxygen species such as superoxide anions (·O2-) and hydrogen peroxide (H2O2) at the lesion site, thereby restoring the redox homeostasis of hair follicles. Additionally, the low-temperature photothermal effect exerted by melanin nano photothermal agents under infrared laser irradiation can effectively stimulate hair follicle cells, enhance follicular metabolic activity, and improve local microcirculation in the hair area. Through the synergistic effects of ROS scavenging, low-level photothermal stimulation, and microcirculation regulation, this multifunctional hydrogel system holds promise for fundamentally improving the follicular microenvironment, promoting healthy hair growth, and thus achieving multi-target precision therapy for AGA.

Cadmium (Cd), as a prevalent environmental heavy metal pollutant, has an incompletely elucidated mechanism of intestinal toxicity following oral ingestion. This study aims to elucidate novel mechanisms underlying cadmium-induced intestinal injury. By establishing a murine model of cadmium exposure, it was found that cadmium not only directly disrupts the intestinal barrier structure but also induces intestinal microbiota dysbiosis. Fecal microbiota transplantation (FMT) experiments confirmed that the dysbiotic microbiota alone is sufficient to provoke intestinal injury, indicating that microbial dysregulation serves as a critical amplifier of cadmium toxicity. Further investigation revealed that cadmium exposure reshapes the intestinal microenvironment and alters the miRNA profile of gut-derived extracellular vesicles (EVs), with miR-125a-5p being significantly enriched in EVs from the cadmium-exposed group. Mechanistically, miR-125a-5p directly targets and suppresses TNFAIP3, a negative regulator of the NF-κB pathway, thereby relieving the inhibition of this signaling axis and driving sustained inflammation and barrier dysfunction, while inhibition of miR-125a-5p effectively blocks this toxic effect. This study is the first to delineate the axis of "cadmium exposure - intestinal microbiota dysbiosis - gut EV - miR-125a-5p - TNFAIP3 - NF-κB pathway activation - intestinal injury", providing new insights for the development of biomarkers and targeted interventions for cadmium-related intestinal disorders.

Diabetic wounds resent a considerable clinical challenge due to impaired healing, which results from persistent inflammation and dysregulated macrophage polarization. This study identifies CITED2 as a critical regulator of diabetic wound repair, primarily through its role in modulating macrophage plasticity. We demonstrate that CITED2 exhibits phase-specific expression during normal wound healing, and its downregulation in diabetic wounds disrupts the transition from M1 to M2 macrophages. Local administration of recombinant CITED2 protein accelerates wound closure by promoting the shift of macrophages toward the anti-inflammatory M2 phenotype, thereby enhancing re-epithelialization, collagen deposition, and angiogenesis. Transcriptomic analysis reveals that CITED2 potentially mediates the activation of PPAR-γ signaling and the upregulation of anti-inflammatory genes. Further immunofluorescence analysis of wound tissues shows an upregulation of anti-inflammatory genes (IL10, Gpnmb, and Nr1d1) and a downregulation of pro-inflammatory genes (IL-6, IL-1β, and TNF-α). Additionally, in vitro experiments indicate that conditioned medium from CITED2-treated macrophages significantly enhances the proliferation and migration capabilities of endothelial cells and fibroblasts. Notably, short-term CITED2 treatment (3 days) achieves comparable efficacy to a 14-day rhFGF therapy. To facilitate clinical translation, we developed a fibrin-thrombin-PEG hydrogel spray (Fib-Thr-PEG-CITED2) that exhibits favorable anti-inflammatory and hemostatic properties, along with demonstrated biosafety. In diabetic mouse wounds, the Fib-Thr-PEG-CITED2 hydrogel spray shows superior wound healing effects compared to CITED2 alone or Fib-Thr-PEG controls. These findings establish CITED2 as a novel therapeutic target and the Fib-Thr-PEG-CITED2 hydrogel as a potential strategy for diabetic wound management.