Journal of Nanobiotechnology最新文献

Background: Doxorubicin (DOX) is one of the most potent chemotherapeutic agents for cancer treatment. However, its cumulative and often irreversible, life-threatening cardiotoxicity significantly limits its clinical applications. While strategies like dose reduction, iron chelation, and liposome encapsulation have aided in mitigating cardiotoxicity to certain extent, they are associated with decreased therapeutic efficacy and potential cancer relapse, the risk of developing secondary malignancy, and the incidence of the Hand-foot syndrome. Exosomes (Exo) are naturally occurring nanoparticles that can be engineered to display targeting moieties on their surface, thereby enhancing drug delivery efficacy. We aimed to develop an exosomal DOX formulation targeting broad epidermal growth factor receptor (EGFR) variants to enhance its anti-tumor efficacy and minimize cardiotoxicity.

Results: The native 53-amino-acid EGF was decorated on the surface of exosomes by genetically engineering exosome-producing A549 cells. The EGF-Exo was effectively internalized by tumor cell lines in a manner dependent on EGFR expression levels, and exhibited enhanced accumulation in xenograft A549 tumors relative to the heart, with minimal cardiac accumulation. When loaded with DOX, these engineered exosomes were rapidly internalized, inducing higher apoptosis in A549 cells compared to liposomal-DOX. Upon systemic administration in an A549 xenograft mouse model, EGF-Exo-DOX exhibited enhanced accumulation in tumors relative to the heart, with minimal cardiac accumulation, significantly reducing tumor burden, mitigating DOX-induced cardiotoxicity, and exhibiting no tumorigenic effects. This favorable therapeutic profile is primarily attributed to DOX-induced apoptosis.

Conclusions: Our findings demonstrate that tumor-derived exosomes engineered with EGF on their surface enable targeted drug delivery to tumors with high EGFR expression. Although the exosomes modestly increase cell proliferation in vitro, the EGF-Exo-DOX formulation exhibits enhanced tumor accumulation relative to the heart, minimal cardiac uptake, and shows no tumorigenic effects in vivo. Compared to Lipo-DOX, a widely used clinical formulation of liposomal DOX in China, EGF-Exo-DOX demonstrates superior cellular uptake, greater induction of tumor cell apoptosis, and improved anti-tumor efficacy. These results highlight the potential of engineered exosomes as a targeted drug delivery platform for patients with EGFR-overexpressing tumors.

Background: PD-1 inhibitors are a promising treatment for melanoma, but over 50% of patients with metastatic melanoma do not respond well. This limited efficacy is partly due to the aberrant vascular structure and immunosuppressive microenvironment in metastatic lung tissue.

Methods: We developed an extracellular vesicle-based delivery system Tanshinone IIA & Icaritin -MPs (TSA&ICT-MPs) that targets lung metastases. In vivo in vitro models, cell experiments, immunofluorescence, immunohistochemistry, flow cytometry, and mass spectrometry flow cytometry were used to validate the efficacy of TSA&ICT-MPs in promoting vascular normalization, enhancing the activity of tumor-infiltrating lymphocytes (TILs), and reducing myeloid-derived inhibitory cell (MDSC) infiltration by modulating the adenosine metabolic pathway.

Results: TSA&ICT-MP contributes to vascular normalization by modulating ELTD1, thereby enhancing TIL infiltration, and reduces adenosine release by targeting ENPP1, thus enhancing anti-tumor immunity. Combining TSA&ICT-MP with α-PD-1 achieved a 70.33% suppression rate of lung metastasis and prolonged survival in murine models. This approach offers a promising strategy to enhance the efficacy of melanoma immunotherapy.

Antibiotics remain the recommended first-line therapy for eradicating Helicobacter pylori infection. However, the harsh gastric physicochemical environment severely limits drug bioavailability, contributing to treatment failure (~10%), gut dysbiosis, and the emergence of antimicrobial resistance. Inspired by H. pylori adhesins binding to gastric epithelial glycan, we developed a biomimetic nanocomposite drug delivery system (BSNG) composed of genetically engineered adhesin-functionalized silk fibroin nanoparticles (BS-NPs) embedded within a fluid silk fibroin hydrogel (FSF-Gel) for targeted anti-H. pylori therapy. BS-NPs exhibit H. pylori-like adhesion to gastric epithelial cells, enabling prolonged gastric retention of over 72 h. FSF-Gel provides conformal coverage of the gastric mucus layer and supports sustained antibiotic release, and prevents acid-induced aggregation of the encapsulated BS-NPs. Upon gastric administration, amoxicillin-loaded BSNG (BSNG@Amo) significantly enhanced both peak drug concentrations and extended therapeutic retention in gastric tissue. In vivo antibacterial studies confirmed that BSNG@Amo achieved superior H. pylori eradication compared to conventional amoxicillin at equivalent doses. Notably, reduced-frequency BSNG@Amo administration maintained therapeutic efficacy while markedly preserving gut microbiota homeostasis. These results highlight BSNG as a precise, long-acting, and microbiota-sparing platform for sustainable gastric antibiotic delivery.

Background: Brain development and plasticity depend on specific microRNA (miRNA) expression patterns across cell types and subcellular compartments. Nevertheless, comprehensive profiling of localized brain miRNAs is still limited by challenges in isolating individual cell types or compartments and in detection sensitivity.

Results: To overcome these limitations, we advanced HIV-1 Gag's ability to bind host miRNAs within Virus-like Particles to develop Synthetic Nano-Particles for Precise endogenous miRNA loading and export (SNaP). Our data establish SNaP's modularity and portability to clinically relevant neural cells, with particle yields matching benchmark packaging cells. The integration of SNaP with a cell-specific promoter enabled lineage-restricted miRNA export, while incorporating a dendritic localization signal improved the specificity of post-synaptic miRNA recovery over traditional synaptosomes. Additional engineering with a miRNA-binding module synergistically increased synaptic miRNA packaging in a sequence-independent manner.

Conclusion: Collectively, this work positions SNaP as a technological advancement supporting the high-resolution, spatially resolved profiling of miRNAs, adaptable to diverse polarized or heterogeneous culture systems.

Periodontitis is a chronic inflammatory condition affecting billions globally, posing a significant public health challenge due to its high prevalence and associated tooth loss. The inflammatory microenvironment engendered by periodontitis can induce cellular senescence and functional impairment in critical reparative cells, such as periodontal ligament stem cells (PDLSCs), severely compromising their osteogenic differentiation potential and thereby obstructing the regeneration and repair of periodontal tissues, particularly alveolar bone. Although existing fundamental treatments, including subgingival scaling, and surgical interventions can partially manage the disease, they exhibit notable limitations in eradicating deep-seated inflammation and effectively promoting structural bone regeneration. Consequently, there is an urgent need to develop novel biological treatment strategies aimed at reversing the senescent state of PDLSCs and enhancing their regenerative capacity. Flufenamic acid (FFA) is a widely utilized non-steroidal anti-inflammatory drug known for its notable anti-inflammatory and osteogenic properties. It holds significant potential for application in periodontal tissue engineering; however, its precise effects and underlying mechanisms remain inadequately understood. In this investigation, FFA effectively reversed the senescent state of periodontal ligament stem cells (PDLSCs), resulting in a marked down-regulation of pro-inflammatory, cellular senescence, and osteoclast differentiation-related markers, alongside an up-regulation of osteogenic differentiation-related markers. Furthermore, FFA significantly inhibited M1 polarization and osteoclast differentiation activity in macrophages and osteoclast precursor cells. Drug target screening and molecular docking analyses indicated that FFA mitigates PDLSC senescence and enhances their osteogenic capacity through activation of the SIRT1 signaling pathway. Additionally, this study employed the biological effects of M1 macrophage membranes to develop biomimetic hybrid nanovesicles (FFA@M1-LPs) designed to respond to inflammatory microenvironments. These findings suggest that FFA could be a promising new drug for periodontitis treatment and offer insights for developing drug delivery strategies to effectively regenerate periodontal tissue.

Photodynamic therapy (PDT) is an effective adjunct treatment for oral squamous cell carcinoma (OSCC). Enhancing photosensitizer targeting and inducing effective cytotoxic T-cell responses through photoimmunotherapy have become key strategies to improve PDT efficacy. Migrasomes, as vesicular structures assembled by TSPAN4 and cholesterol microdomains, are implicated in immune escape and are emerging as sensitization targets for PDT. Here, we report a biomimetic nanoplatform, MOF-919@CCM, that combines enhanced tumor-cell membrane adhesion with light-controlled cholesterol degradation. Cloaking with a homologous cancer-cell membrane (CCM) imparts specific adhesion to tumor cells and improves targeted delivery of the photosensitizer. Moreover, the transition-metal nodes of MOF-919 exhibit peroxidase- and catalase-like activities that alleviate tumor hypoxia and, under laser irradiation, effectively reduce cellular cholesterol levels. Experiments further revealed that PDT based on MOF-919@CCM markedly suppresses migrasome formation via effective degradation of cholesterol and promotes CD8⁺ T-cell infiltration and cytotoxic activity against tumor cells. This work develops a targeted PDT approach using MOF-919@CCM and provides a new strategy for the immunotherapy of OSCC.

The unique pathological microenvironment of periodontitis poses significant challenges to conventional therapies and drives the development of advanced treatment strategies. Engineered nanozymes as multifunctional nanomaterials offer promising alternatives for actively modulating disease microenvironments. Compared with traditional nanozymes, engineered nanozymes are rationally designed through elemental doping, heterojunction construction, and surface modification, leading to increased catalytic efficiency, microenvironmental responsiveness, and multifunctional integration. This review systematically discusses three representative engineering strategies for the treatment of periodontitis: antibacterial, anti-inflammatory, and regenerative approaches. Furthermore, we introduce the concept of "hierarchical therapy," which integrates these strategies into a unified framework for achieving more precise and effective therapeutic outcomes. Finally, this review highlights the current challenges faced by engineered nanozymes, including biosafety concerns, catalytic durability, and barriers to clinical translation. Overall, this study aimed to provide a comprehensive overview of the rational design, functional integration, and therapeutic potential of engineered nanozymes in periodontal applications, offering valuable guidance for the development of intelligent nanoplatforms for future precision oral medicine.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation, cartilage destruction, and bone loss. Current therapeutic approaches are often limited by short drug half-life, insufficient local drug release, and substantial systemic side effects.In this study, we developed a composite thermosensitive hydrogel system that integrates in situ gelation, sustained drug release, and multitarget therapeutic effects for localized precision treatment of RA.The system consists of a thermosensitive hydrogel matrix composed of hydroxypropyl methylcellulose (HPMC), hyaluronic acid (HA), and glycerol, in which gelatin methacryloyl (GelMA) hydrogel microspheres are embedded. The microspheres efficiently encapsulate Drynaria rhizome-derived extracellular vesicles (DR-EVs), while sinomenine is incorporated into the thermosensitive hydrogel to enhance anti-inflammatory activity. Characterization by transmission electron microscopy (TEM), scanning electron microscopy (SEM), nanoparticle tracking analysis (NTA), rheological measurements, and Fourier-transform infrared spectroscopy (FTIR) confirmed the intact morphology of DR-EVs, the uniform porous structure of the microspheres, and the favorable thermoresponsive gelation behavior and controllable degradation properties of the composite system. Functional assays revealed that, in vitro, the system effectively suppressed TH17 cell proliferation, promoted Treg cell differentiation, and inhibited M1 macrophage polarization.Meanwhile, it upregulated osteogenesis-related genes (Runx2, BMP2) and inhibited osteoclast formation. In a collagen-induced arthritis (CIA) rat model, the system significantly alleviated joint swelling, restored cartilage and bone architecture, and suppressed the progression of synovial inflammation. In summary, this composite thermosensitive hydrogel system possesses injectability, thermoresponsive behavior, prolonged release capability, and multiple biological activities, offering a safe, efficient, and controllable novel strategy for localized precision therapy of RA.

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by progressive fibrosis and poor prognosis, with no current therapies capable of reversing the fibrotic changes. The aberrant repair driven by fibroblast activation and an inflammatory microenvironment results in irreversible IPF. In this work, a macrophage-derived apoptotic body delivery system (SA + NAC@AB) co-loaded with sodium arsenite (SA) and N-acetylcysteine (NAC) was developed to exert synergistic antifibrotic activity against IPF via coordinated regulation of TGF-β1 signaling and inflammation. Apoptotic bodies derived from macrophages inherit inflammation-homing capability, enabling targeted delivery to fibrotic lesions. In vivo evaluation in a bleomycin-induced IPF mouse model demonstrated that SA + NAC@AB effectively targeted the lungs, significantly improved body weight and survival, and alleviated pulmonary fibrosis. Immunofluorescence and Western blot analyzes revealed that SA + NAC@AB reduced Smad2/3 phosphorylation and M2 macrophage polarization, indicating regulation of the TGF-β1/Smad2/3 pathway and inflammation as part of its mechanism of action. Furthermore, in vitro studies validated the enhanced efficacy of SA + NAC@AB, which significantly promoted fibroblast uptake, thereby potentiating its inhibitory effects on fibroblast viability, as well as TGF-β1-induced migration and differentiation. In conclusion, our study demonstrates that SA + NAC@AB represents an effective therapeutic strategy for IPF, offering a promising novel approach by modulating both the TGF-β1/Smad2/3 signaling pathway and the inflammatory response.

The skin is a three-dimensional organ composed of multilayered tissues, in which the epidermis, dermis, and subcutaneous adipose layer cooperate to maintain protection, thermoregulation, and repair. Although recent advances in tissue-engineered skin substitutes have improved cutaneous regeneration, strategies that simultaneously promote dermal and adipose restoration remain limited. Here, we developed a bi-layered tissue-engineered skin scaffold with dermal-adipose architecture fabricated by conjugate electrospinning of polycaprolactone solutions containing acellular dermal matrix (ADM) or decellularized adipose tissue (DAT). The construct exhibited dual bioactivity: stimulating fibroblast proliferation and collagen remodeling in the dermal layer, while promoting adipose-derived stem cell proliferation and adipogenesis in the adipose layer. In a full-thickness nude rat wound model, the scaffold enhanced vascularization, modulated inflammation, and accelerated regeneration of both dermal and adipose tissues. These findings demonstrate a versatile platform for multilayered skin tissue engineering and provide new insight into dermal-adipose synergistic regeneration.