International Journal of Nanomedicine最新文献

The tumor microenvironment (TME) is a dynamic and heterogeneous ecosystem whose abnormal vasculature, dense extracellular matrix, metabolic reprogramming and immunosuppression collectively hinder drug penetration, drive therapeutic resistance and limit responses to immunotherapy. TME-responsive nanomedicine provides an emerging toolbox to both monitor and actively remodel the microenvironment for precision cancer therapy. In this narrative review, we first summarize key pathological features of the TME and their impact on drug delivery across classical barriers, including the blood-brain, cutaneous and ocular interfaces, as well as circulating and bone-marrow niches in hematologic malignancies. We then discuss design principles of endogenous and exogenous stimuli-responsive nanoplatforms, and how these systems enable TME monitoring via liquid biopsy, spatial multi-omics and real-time imaging, and TME modulation through metabolic reprogramming, immune activation, vascular normalization and extracellular-matrix remodeling. Finally, we highlight major translational challenges and future opportunities, emphasizing the roles of artificial intelligence, multiscale and quantum-inspired modeling, and closed-loop theranostic strategies in optimizing TME-responsive nanomedicines for clinically meaningful benefit.

In recent years, plant-derived extracellular vesicle-like nanoparticles have garnered significant interest as promising therapeutic agents and delivery vehicles, owing to their biocompatibility and multifaceted bioactivity. Among these, extracellular vesicles derived from Aloe species (A-EVs) have shown considerable potential in promoting tissue repair. However, a consolidated overview linking their physicochemical properties to in vivo reparative functions and clinical translatability is still lacking. This review systematically summarizes current methods for isolating and characterizing A-EVs, highlighting the technical variability that challenges standardization. Evidence is synthesized demonstrating that A-EVs facilitate injury repair through integrated mechanisms, including potent antioxidant effects via Nrf2/HO-1 pathway activation, anti-inflammatory action via macrophage polarization and NF-κB suppression, and the promotion of cellular proliferation and migration. Notably, emerging research reveals their unique capacity to induce immunogenic cell death (eg, pyroptosis) in diseased tissues, setting them apart from many other plant EV sources. Compared to EVs from other medicinal plants, A-EVs offer a distinctive combination of anthraquinone-enriched cargo, pro-healing protein profiles, and mucoadhesive properties, making them particularly suited for wound and gastrointestinal repair. Despite low immunogenicity and a natural propensity for drug encapsulation, major hurdles-such as scalable production, pharmacokinetic profiling, and rigorous safety assessment-must be overcome to advance clinical translation. By critically evaluating recent progress and existing gaps, this review clarifies the mechanistic basis for A-EVs' reparative effects and provides a rationale for their future development as standardized, next-generation nanotherapeutics for regenerative medicine.

Introductions: Gastric cancer with peritoneal metastasis (GCPM) carries a poor prognosis, constrained by inadequate drug delivery, systemic toxicity, and an immunosuppressive microenvironment. We developed E3C4, a single mRNA-lipid nanoparticle (LNP) co-encoding EpCAM×CD3 and Claudin18.2×41BB bispecific antibodies (BsAbs), to achieve localized dual-antigen T cell co-activation against GCPM.

Methods: E3C4 was prepared by co-encapsulating m¹Ψ-modified mRNAs using ionizable lipids. Functional characterization included surface plasmon resonance (SPR) for binding affinity, T cell-dependent cytotoxicity (TDCC), and 4-1BB reporter assays. In vivo efficacy was evaluated in PBMC-humanized mice bearing subcutaneous or orthotopic NCI-N87 tumors. Immune infiltration and cytokine release were analyzed via flow cytometry and ELISA. Safety was assessed in C57BL/6J mice through acute and repeated-dose toxicity studies.

Results: Consequently, E3C4 exhibited optimal particle size and encapsulation efficiency. SPR confirmed high affinity for both BsAbs (KD ~10^-10 M). Synergistic T cell activation achieved 80.9% cytotoxicity in vitro, significantly surpassing EpCAM×CD3 alone (29.1%, P<0.001). In subcutaneous models, 3 μg E3C4 induced 98.5% tumor growth inhibition with enhanced T cell infiltration and granzyme B expression. Intraperitoneal delivery enabled 96.4% tumor-localized expression, yielding superior efficacy over recombinant BsAbs in orthotopic models. E3C4 showed no mortality or cytokine release syndrome, with only transient elevations in IL-6, AST and ALT, as well as a >10% body weight loss that resolved within 2 weeks. The maximum tolerated dose exceeded the therapeutic dose by >200-fold.

Conclusion: E3C4 constitutes a localized, synergistic platform that enables dual-antigen T cell co-activation within the peritoneal cavity. This approach maximizes antitumor efficacy while circumventing systemic toxicity, offering a novel immunotherapeutic strategy for GCPM.

Cancer remains one of the leading causes of death worldwide, with diagnosis and treatment continuing to pose significant challenges. In recent years, iron-based nanomaterials (iron oxide-based nanomaterials, iron-based complex conjugates) have garnered unprecedented attention due to their excellent functionality, superior biocompatibility and potential for multifunctional integration. Due to the non-specific nature of radionuclides. Their integration with nanomaterials offers promising opportunities for precise cancer diagnosis and effective treatment by enabling targeted delivery, controlled release, and synergistic combination therapies. This review systematically elucidates the latest advancements in radiolabeled iron-based nanomaterials for cancer diagnosis and therapy, with a focus on radiolabeling methods, multimodal imaging, and the combination of radiotherapy with various treatment modalities, including photothermal therapy (PTT), magnetic hyperthermia therapy (MHT), photodynamic therapy (PDT), immunotherapy (IT), and chemodynamic therapy (CDT). Finally, the prospects for the development of radiolabeled iron-based nanomaterials are discussed, along with key research priorities for the future.

The growing use of nanomaterials (NMs) in consumer, medical and industrial products raises significant concerns about human exposure and the risk of cardiovascular toxicity. This narrative review synthesizes three critical and interconnected aspects of nanomaterial-induced cardiotoxicity-risk assessment models, mechanisms, and mitigation strategies-with the overarching goal of advancing fundamental knowledge and supporting the development of safer NMs. A variety of assessment models are explored, ranging from traditional in vitro and in vivo systems to emerging organ-on-a-chip platforms. A tiered, decision-driven strategy for model selection is based on risk-stage, objective-orientation, evidence complementarity, and ethical optimization, with emphasis on the critical need to assess toxicity under pathological conditions. Key mechanisms include oxidative stress, mitochondrial dysfunction, inflammatory responses, disruption of ion homeostasis, and induction of cell death. The specific pathway is often dictated by the physicochemical properties of nanoparticle. Potential mitigation strategies include surface engineering, elemental substitution/doping, morphological design, the use of chelating agents/antioxidants, and adopting Safe-by-Design principles. Interdisciplinary collaboration is crucial during the developmental phase to balance the immense application potential of NMs with the imperative to address their associated toxicity challenges.

Purpose: Chemodynamic therapy (CDT) has emerged as a promising cancer treatment strategy leveraging tumor microenvironment conditions to generate reactive oxygen species (ROS) through Fenton-type reactions. This study reports the synthesis, in-depth characterization, and biological evaluation of novel manganese-based zeolitic imidazolate framework (ZIF) nanoparticles, ie, Mn-rods, as a carrier-free potential CDT platform with exceptionally high manganese loading.

Methods: Mn-rods were synthesized through coordination of Mn²⁺ ions with 2-methylimidazolate and characterized using transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR), and inductively coupled plasma optical emission spectroscopy (ICP-OES). Two human non-small cell lung cancer lines (A549 and Calu-3) were used to evaluate nanoparticle internalization and therapeutic response was assessed using cell viability assays, ROS generation measurements, and rescue experiments with pathway-specific inhibitors.

Results: The synthesized Mn-rods exhibited a rod-shaped morphology (226 ± 93 nm length x 26.5 ± 9.5 nm width) with an exceptional Mn²⁺ loading of 50 wt.%, surpassing existing manganese-based systems. Both A549 and Calu-3 cells internalized Mn-rods, however, only A549 cells exhibited marked dose-dependent cell viability reduction, highlighting the influence of cellular phenotype on therapeutic response. Mechanistic studies suggest that Mn-rods induce ferroptosis-like cell death in A549 cells through lipid peroxidation and redox imbalance, independent of apoptosis, necroptosis and iron-mediated pathways. Rescue experiments with ferroptosis inhibitors (ferrostatin-1 and liproxstatin-1) confirmed the lipid ROS-driven mechanism, further supported by increased intracellular ROS levels and progressive membrane damage.

Conclusion: These findings establish Mn-rods as potent CDT agents whose efficacy is dictated by tumor cell oxidative vulnerability. Understanding such cell-specific responses is critical for optimizing nanoparticle design and tailoring therapeutic strategies in heterogeneous tumor environments. Future studies should extend these investigations across diverse cancer models to refine their translational potential.

Purpose: Chronic Obstructive Pulmonary Disease (COPD) is a major global health issue characterized by progressive airflow limitation, chronic inflammation, and recurrent infections. Current treatments largely alleviate symptoms but fail to simultaneously address infection-driven and inflammation-driven disease progression. Exosome-based strategies offer a promising alternative, and plant-derived exosomes possess distinct advantages, including low immunogenicity, natural abundance, and simple isolation compared with mammalian exosomes.

Methods: We developed a novel dual-functional nanotherapeutic agent by loading ampicillin into exosomes derived from Trigonella foenum-graecum. The resulting ampicillin-loaded exosomes (Exos-AM) harness the natural bioactivity and biocompatibility of plant exosomes to improve drug stability and cellular delivery. The therapeutic efficacy of Exos-AM was evaluated in a murine COPD model induced by lipopolysaccharide (LPS) instillation, cigarette smoke exposure, and P. aeruginosa infection.

Results: In vitro, Exos-AM exhibited potent antibacterial activity against S. aureus, E. coli, and P. aeruginosa, while promoting macrophage polarization toward the anti-inflammatory M2 phenotype, thereby alleviating inflammation and attenuating fibrotic responses. Transcriptomic analysis further revealed that Exos-AM modulated macrophage activation through suppression of the NF-κB and MAPK signaling pathways, providing mechanistic insight into its anti-inflammatory effects. In vivo, Exos-AM treatment significantly improved lung histopathology and enhanced bacterial clearance.

Conclusion: Our findings underscore the promise of plant-derived exosomes as versatile drug delivery platforms and position Exos-AM as a compelling therapeutic strategy for COPD by concurrently targeting infectious and inflammatory drivers.

Eye diseases are a major global public health issue causing vision impairment and blindness. The eye's physiological barriers limit traditional drug delivery methods, resulting in low bioavailability, high risks, and poor patient compliance. Nanotechnology offers a revolutionary solution that can enhance the abilities of drugs in corneal retention, barrier penetration, targeted delivery and controlled release to improve efficacy and reduce side effects.This paper reviews the latest advances in nanotechnology for treating ophthalmic diseases. It covers primary nanocarrier systems (lipid, polymeric, carbon-based, and metallic/metallic compound nanoparticles), detailing their characteristics and ocular application potential. It also focuses on specific applications: nanomedicine for anterior segment disorders (cataracts, dry eye, inflammatory conditions) and posterior segment diseases (age-related macular degeneration, diabetic retinopathy, retinal vein occlusion), breakthroughs in delivering anti-VEGF drugs, and innovative applications in treating refractory ocular tumors. Additionally, it explores nanotechnology's prospects in ocular tissue regeneration and retinal gene therapy. Finally, the paper discusses challenges in clinical translation, including standardization, biosafety evaluation, and regulatory approval, and offers an outlook for future development.

Background: The tumor microenvironment (TME) composition is among the critical events leading to the poor prognosis of head and neck cancers. TME includes immune cells, tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAF), and other non-cancerous cells, which contribute to therapeutic outcome. The heterogeneity of the TME offers a multitude of potential targets for photodynamic therapy (PDT). Advanced 3D models that closely mimic the microenvironment are a promising tool to study tumor-stroma interactions, TAM plasticity and their impact on Foslip^®-PDT outcome.

Objective: The aim of this study was to assess the effect of Foslip-PDT on photo-induced macrophage re-education in 3D tri-culture model composed of cancer cells, CAFs, and macrophages.

Methods: A 3D model was established using FaDu cancer cells, MeWo fibroblasts, and PMA-differentiated U937 macrophages. The spheroids were characterized using immunochemistry, immunofluorescence, and qPCR. Foslip-based photoirradiation was applied to spheroids at different fluences to evaluate the photoinduced cell death. Macrophage phenotypes were assessed by flow cytometry.

Results: The 3D tri-culture model displayed hallmarks of stromal-tumor interactions, including CAF clustering, macrophage infiltration (~30-40%), and epithelial-mesenchymal transition. Macrophages in the spheroids had prevailing M2 phenotype as deduced from overexpression of immunosuppressive markers (CD163, PDL-1, IL-10). The liposomal photosensitizer Foslip accumulated 2 to 3 times more in macrophage-enriched spheroids, however, PDT induced similar levels of cell death in all tested models. At the same time, Foslip-PDT produced immunomodulatory effect in tri-culture model characterized by the increase of CD80-M1 marker expression and the decrease in the expression of the CD206-M2 marker.

Conclusion: The 3D tri-culture model integrated essential features of the HNSCC microenvironment. Foslip-PDT was effective in reprograming M2 macrophages to tumor-killing M1 macrophages. This study opens the way to combine direct tumor damage with TME modulation.

Developing optimal drug delivery carriers to enhance the pharmacokinetics of therapeutic agents and mitigate toxicity to normal cells remains a pivotal focus in medical research. Extracellular vesicles (EVs) have emerged as a highly promising platform for drug delivery, owing to their unique biological properties. Through intrinsic biogenesis pathways, EVs can selectively encapsulate genetic material, proteins, cytokines, and other bioactive components from donor cells. They subsequently mediate intercellular communication and regulate target cell behavior via humoral transport, surface protein interactions, membrane fusion, and other mechanisms-biological features that lay the foundation for their potential in therapeutic delivery. In recent years, EVs have attracted tremendous research interest due to their excellent biocompatibility, nanoscale size, low immunogenicity, facile modifiability, and versatile capacity to load various therapeutic agents. In this review, we analyse strategies for improving the quality control of drug-loaded EVs across multiple dimensions, specifically including the selection of EVs sources, control of isolation and purification, control of drug-loading strategies, and evaluation strategies after EVs drug loading, we also report the latest preclinical and clinical studies on the use of EVs as drug delivery systems for small-molecule drugs, nucleic acids, and proteins in disease treatment.