Journal of Nanobiotechnology最新文献

The efficacy of radiotherapy for brain tumors is limited by tumor cell radio-resistance and the immunosuppressive microenvironment, which often counteracts the immunogenic effects of radiation-induced antitumor responses. To address this, we developed statherin-enriched engineered outer membrane vesicles (OMVs), co-labeled with the radionuclide ¹³¹I and loaded with the metabolic inhibitor methotrexate (MTX), termed ¹³¹I-O/M-P, to enable integrated radiotoxicity, metabolic intervention, and immune activation. Upon delivery of ¹³¹I-O/M-P to the tumor site, ¹³¹I promptly emits β-rays that induce DNA double-strand breaks, triggering immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs), thereby initiating antitumor immune responses. Subsequently, the released MTX is internalized by tumor cells, where it inhibits dihydrofolate reductase (DHFR), blocks nucleotide synthesis, impairs DNA repair capacity, and exacerbates DNA damage accumulation, thereby further promoting apoptosis and immune activation. Meanwhile, the intrinsic adjuvant properties of OMVs synergize with the ICD response to enhance T cell activation and infiltration. In both subcutaneous and orthotopic brain tumor mouse models, ¹³¹I-O/M-P significantly enhanced CD8⁺ T cell infiltration, reduced T cell exhaustion phenotypes, and suppressed tumor growth. In summary, we present a temporally coordinated radio-metabolic-immunotherapy strategy, offering a novel therapeutic approach for advancing radio-immunotherapy in brain tumors.

Melanoma has a high incidence and mortality, and current therapies are limited. Here, we developed TCPC, an ER-targeted nanomedicine guided by omics analysis. It consists of curcumin-loaded PEG-PCL nanomicelles coated with a Tannic acid-Cu metal-polyphenol network. Guided by clinical transcriptome mining, we identified ER-stress vulnerabilities to inform material design. RNA-seq and imaging confirmed that TCPC preferentially accumulates in melanoma cells and localizes to the ER. TCPC markedly elevates CHOP expression, which triggers ER Ca²⁺ release, mitochondrial dysfunction, ROS accumulation, and apoptosis. Functionally, TCPC significantly suppresses cell viability, migration, and invasion in vitro. In melanoma xenografts, systemic TCPC treatment slows tumor growth, enhances intratumoral CHOP and Cleaved caspase-3, and induces apoptosis without systemic toxicity. Moreover, pharmacogenomic analyses revealed that CHOP upregulation correlates with increased sensitivity to several agents, and molecular docking highlighted Irinotecan and JQ1 as potential synergistic partners with TCPC. Collectively, this work demonstrates that nanomedicine guided by omics can couple organelle-specific delivery with ER-stress amplification to achieve potent antitumor efficacy. Overall, this work establishes an omics-guided materials strategy that integrates organelle-targeted delivery with ER-stress amplification for effective melanoma therapy.

Chemotherapy is the primary clinical treatment for leukemia, while its effectiveness is often limited due to undesired off-target effects and the reduced sensitivity of leukemia cells to chemotherapeutic agents. Therapies capable of targeting the bone marrow and addressing the acidic tumor microenvironment are anticipated to improve treatment efficacy. Here, we presented biomimetic cell membrane-decorated calcium carbonate nanoparticles co-loaded with asparaginase and metformin (AMNPs@CM) for bone marrow-targeted therapy of leukemia. The biomimetic cell membrane coating facilitated significant accumulation of AMNPs@CM in the bone marrow, where the nanoparticles released the payloads in response to the acidic tumor microenvironment. The released asparaginase and metformin could synergically induce mitochondrial dysfunction in leukemia cells, leading to inhibited cell proliferation and enhanced apoptosis. Thus, our stratagem could effectively inhibit tumor burden and prolong survival in a C1498 leukemia-bearing mouse model. These results indicate the potential of the AMNPs@CM as a bone marrow-targeted delivery platform for combination therapy in the treatment of leukemia.

Excessive accumulation of reactive oxygen species (ROS) and dysbiosis of the gut microbiota are pivotal contributors to the pathogenesis of inflammatory bowel disease (IBD) and associated fibrosis. In this study, a microfluidic approach was utilized to fabricate a multifunctional therapeutic microsphere system by encapsulating hollow mesoporous cerium oxide nanoparticles (HCeO₂) loaded with KP1 short peptides-specific inhibitors of the TGF-β/Smad signaling pathway. The resulting composite formulation (KP1@HCeO₂@SAM) was designed to achieve synergistic antioxidant, anti-inflammatory, and antifibrotic effects. The developed microspheres exhibited prolonged intestinal retention and effectively modulated gut microbiota composition, increasing the relative abundance of probiotic species by over sevenfold. Moreover, they demonstrated remarkable reactive oxygen species (ROS) scavenging efficiency (> 95%) and significant inhibition of fibrotic signaling cascades. In dextran sulfate sodium (DSS)-induced murine colitis models, treatment with the microspheres led to a substantial reduction in Disease Activity Index (DAI) (> 76%), restoration of intestinal barrier integrity (> 90%), and mitigation of fibrotic progression, as indicated by a 66% decrease in α-SMA expression. These findings establish a novel and integrative therapeutic platform for the effective management of IBD.

Bloodstream infections (BSIs) are life-threatening conditions with rising mortality, urgently requiring rapid pathogen identification to guide timely antibiotic therapy. Current methods (phenotypic identification, MALDI-TOF MS, molecular techniques) are faced with limitations in cost, turnaround time and accessibility. In this study, it was discovered that the drying of microbial suspensions on slides could lead to species-specific desiccation patterns, which reflects the physicochemical properties and complex interactions of microorganisms during evaporation. Inspired by this interesting phenomenon, an AI-powered platform is proposed for rapid pathogen identification through automated analysis of these patterns. By establishing an image dataset comprising 10,055 desiccation patterns of common BSIs pathogens (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Enterococcus faecium and Candida albicans), a ResNet-34 deep learning model is trained, achieving a classification accuracy of 91.8% and an area under the receiver operating characteristic curve (AUC-ROC) of 0.99. Following pure culture, identification is completed within 5 min after a simple drying step at 40 °C. With its minimal sample requirement, low cost, and operational simplicity, this platform demonstrates significant potential as a point-of-care diagnostic tool, particularly in resource-constrained regions. This technology offers a promising strategy to combat BSIs and improve patient outcomes.

Maintaining a balanced polarization of microglia is one of the most potential therapeutic approaches for diabetic retinopathy (DR). However, reliable, sustained, effective, and controllable microglial regulation still faces formidable challenges. Here, inspired by the bioavailability and modifiability of extracellular vesicles (EV), we developed an interleukin 4 (IL4)-encapsulated and M1 microglia-targeting EV platform (IL4@CHHSSSARC-EV) for rescuing inner blood-retina barrier (iBRB) deterioration in DR. Delivery of IL4 via IL4@CHHSSSARC-EV enhanced not only the stability of IL4, but also the efficacy of anti-inflammatory phenotype (M2) shift in vitro and in vivo due to their selectivity to pro-inflammatory (M1) microglia. Treatment with IL4@CHHSSSARC-EV significantly ameliorated pathological angiogenesis and iBRB breakdown caused by hypoxia and ischemia in oxygen-induced retinopathy models, and potently minimized leakage, bleeding, lesions, pericyte loss and leukocyte adherence of vascular network in streptozotocin-induced diabetic mice with a high safety profile. Mechanistically, IL4@CHHSSSARC-EV facilitated microglial phagocytic capacity through GAS6-MERTK signaling, thereby engulfing aberrant vessels and disrupting the reciprocal crosstalk between microglia and pathological vasculature. Our study demonstrated that engineering EV as an enduring, efficient and safe implement for manipulating microglia provided a potential strategy for a rebalanced immune profile in DR.

Liver fibrosis, caused by various chronic liver injuries, is one of the major causes of morbidity and mortality worldwide, but there is no efficient treatments in clinic until now. Cell-cell interactions in the injured liver microenvironment play critical roles in hepatic stellate cells (HSCs) activation and excessive extracellular matrix (ECM) deposition, but the exact mechanism involved and specific therapies remain elusive. Here, we report that an extracellular vesicles (EVs)-mediated profibrotic vicious circle might contribute to HSCs activation during the early stages of liver fibrosis development. In brief, increased EVs secretion was observed in patients with liver cirrhosis, mice with liver fibrosis, and injured hepatocytes, whereas pharmacological inhibition of EVs secretion partially alleviated liver fibrosis in mice in vivo. However, the injured hepatocytes-derived EVs (IH-EVs) alone only promoted HSCs proliferation but not ECM deposition. The robust activation of HSCs requires the participation of liver macrophages, which can engulf IH-EVs and secrete various pro-inflammatory and pro-fibrotic factors, thereby sustaining hepatocytes injury and providing costimulation signals to promote HSCs activation and excessive ECM production. Mechanistically, IH-EVs might synergize with macrophages to promote HSCs proliferation by activating the PI3K-AKT and JAK-STAT pathways. We further developed a liver-targeted dual-drug delivery system using normal liver tissue-derived EVs (LT-EVs), which display significant antifibrotic effects in vivo by synergistically suppressing liver EVs secretion and macrophages activation. This study reveals an endogenous EVs-mediated pro-fibrotic mechanism in early liver fibrosis, and provides a potential therapeutic strategy for treating liver fibrosis.

Bladder cancer (BC) remains a prevalent urothelial malignancy characterized by high recurrence and mortality rates, severely compromising patients' quality of life. Current intravesical chemotherapies, although locally administered, are limited by rapid renal excretion and poor tumor accumulation, which undermines treatment efficacy. Moreover, these conventional agents often cause immunosuppression, further diminishing therapeutic outcomes. To address these challenges, we developed MC/Pep, an innovative amphiphilic peptide-based nanoplatform that self-assembles into spherical nanoparticles capable of codelivering mitoxantrone (MT) and cinnamaldehyde (CA). A key innovative feature of this system is its matrix metalloproteinase 2 (MMP2)-responsive structural transformation, which triggers morphological rearrangement into highly aggregated nanostructures within the tumor microenvironment, enabling enhanced targeted accumulation and retention. In addition to improving drug delivery, MC/Pep induced endoplasmic reticulum oxidative stress-mediated immunogenic cell death (ICD) through the triggering of reactive oxygen species (ROS) generation via intracellular redox reactions. MC/Pep also promoted the production of mitochondria-derived ROS by inducing changes in mitochondrial membrane permeability, thereby synergistically enhancing the ICD effect. This system induced the ectopic displacement of calreticulin (CRT) and the exocytosis of high-mobility group protein B1 (HMGB1) and facilitated DC maturation and T-cell activation in vivo, thereby eliciting an antitumor immune response. Owing to its promising pharmacokinetic properties, tumor-targeting ability, and ability to enhance both immunomodulation and drug accumulation, MC/Pep represents a novel and clinically promising nanotherapeutic strategy for BC, offering a viable path toward translation in immunotherapy-enhanced chemotherapy.

Despite the widespread use of emergency coronary reperfusion therapy, effectively managing reperfusion-induced myocardial injury remains a major clinical challenge. Neutrophil infiltration and the release of damage-associated molecular patterns (DAMPs), particularly the alarmin S100A8/A9, play pivotal roles in driving post-ischemic inflammation and exacerbating myocardial damage. To address this, we developed engineered neutrophil membrane-coated nanoparticles (ENM/RNA NPs) co-loaded with S100A9-targeting siRNA and G0-C14 to alleviate ischemia/reperfusion-induced cardiomyocyte injury. These biomimetic NPs leverage lymphocyte function-associated antigen-1 (LFA-1) overexpression on engineered neutrophil membranes to achieve inflammation-responsive myocardial targeting, thereby competitively blocking intercellular adhesion molecule-1 (ICAM-1)-mediated neutrophil-endothelial interactions and subsequent infiltration. Moreover, hemagglutinin (HA) expressed on the surface of ENM/RNA NPs facilitates endosomal escape, preserving siRNA integrity and function. In a murine model of myocardial ischemia/reperfusion injury (MI/RI), intravenously administered ENM/RNA NPs selectively accumulated in ischemic myocardium and significantly downregulated S100A9 expression in both serum and cardiac tissues. This intervention effectively attenuated neutrophil recruitment, reduced infarct size, and improved cardiac function. Collectively, our findings demonstrate a biomimetic siRNA delivery system based on neutrophil membrane engineering that modulates the S100A8/A9 axis, offering a promising targeted therapeutic strategy for MI/RI.

DNA nanotechnology offers a powerful alternative in biomedical areas yet a simple and general strategy to engineer DNA-based nanomedicine bearing high and adjustable drug-loading capacity and stability remains challenging. Herein, we report that it is a ubiquitous property for plain DNA (except for guanine-rich sequences) to assemble with the widely used anticancer drug, doxorubicin hydrochloride (DOX), into well-defined nanospheres via thermal annealing, which circumvents additional adjuvants (e.g., metal ions) or chemical modifications of DNA (e.g., hydrophobic conjugation). Experimental results and molecular dynamics simulation reveal that shape remolding is a result of heat-promoted intra-particle interactions. We demonstrate that the nanospheres display high DOX-loading capacity and feasible size controllability, and the generality of this approach is also established with diverse functional cationic aromatics (drugs, fluorescent dyes and aggregation-induced emission luminogens). Finally, we construct a carrier-free nanomedicine by assembling DOX with a therapeutic antisense oligonucleotide, and the combined therapeutic performance is demonstrated in vitro and in vivo.