Publications

Bioresponsive engineered nanoparticles for immunomodulation

Publications /

Abstract

Background

Nanoparticles (NPs) have emerged as highly efficient drug delivery vehicles. NPs are characterised by their ability to safeguard drugs, enhance stability, prolong durability, and facilitate targeted tissue delivery. Moreover, NPs can be customised to either stimulate or suppress immune responses while evading immune detection.

Main body

An increasing body of research demonstrated the therapeutic advantages of delivering various substances via surface-engineered NPs particularly in targeting immune cells. A broad spectrum of nanomaterials has been recognised for their superior ability to elicit immune responses, thereby enhancing disease prevention and therapeutic outcomes in vivo. In this comprehensive review, we discuss the impact of bioresponsive NPs on immunostimulation, immunomodulation, and immunosuppression. Particular focus is placed on how the physiochemical properties of these NPs influence the interaction between immune cells and host tissues, thereby achieving the desired immune regulation to combat various human diseases while reducing immunotoxicity. Additionally, we examined immune-inspired and immune-mediated strategies for the targeted delivery of NPs to specific sites within the body. Finally, we highlight the importance of understanding and focusing on immune cell trafficking mechanisms, as deeper insights into these processes may guide the rational design and fabrication of NPs capable of specifically targeting altered immune pathways under pathological conditions. This review offers an in-depth understanding of the diverse roles of bioresponsive NPs in immune regulation and targeted drug delivery, aiming to advance therapeutic strategies for a wide range of human diseases.

Conclusion

Nanomaterials possess significant immunomodulatory capabilities, enhancing both disease prevention and therapeutic efficacy in vivo, yet their clinical translation is hindered by complex fabrication methods and high production costs. Future efforts must focus on simplifying synthesis and improving cost-efficiency to facilitate their adoption in clinical practice.

Full Article: https://link.springer.com/article/10.1186/s12916-025-04305-6

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Advances in RNA-based cancer therapeutics: pre-clinical and clinical implications

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Abstract

Cancer therapy has been revolutionised by the emergence of RNA-based therapeutics, providing several strategies and mechanisms to regulate gene expression via messenger RNA (mRNA), small interfering RNA (siRNA), microRNAs (miRNA), antisense oligonucleotides (ASOs), and RNA aptamers. The present review highlights the recent advances in the preclinical development and clinical applications of RNA-based therapeutics, focusing on the delivery strategies, biological targets, and pharmacological optimisation, together with key clinical data. mRNA therapeutics, especially those adapted from vaccine platforms are being developed for the cancer immunotherapy and protein replacement, while siRNAs and ASOs enable highly specific gene silencing and splice correction. miRNA therapies show potential for diverse oncogenic pathway control, despite ongoing challenges in the delivery and specificity. RNA aptamers are obtaining attention as tumor-targeting agents in the drug delivery systems. Progress in lipid nanoparticles, chemical modifications, and tissue-specific delivery has improved the stability and efficacy of these agents. Early-phase clinical trials report encouraging outcomes in both solid tumours and haematologic malignancies, particularly in overcoming resistance and modulating the tumor microenvironment (TME). Although challenges remain in scalability, immune activation, and deep-tumour penetration, RNA-based strategies are advancing towards integration into clinical oncology. Continued refinement of delivery technologies and targeted trial designs will be critical for translating these therapies into effective, personalized cancer treatments.

Full Article: https://link.springer.com/article/10.1186/s12943-025-02463-y

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Fungal microbiota signatures anticipate neoadjuvant immunochemotherapy outcomes in esophageal cancer

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Abstract

Background Predicting neoadjuvant immunochemotherapy (NICT) response remains a critical challenge in esophageal squamous cell carcinoma (ESCC) management. While the gut bacteriome’s role in immunotherapy has been established, the mycobiome’s predictive potential remains largely unexplored. This study investigated whether gut fungal signatures could serve as reliable biomarkers for NICT response prediction in patients with ESCC.

Methods We performed internal transcribed spacer 2 sequencing on 155 fecal samples from 68 patients with ESCC (pre-NICT and post-NICT) and 19 healthy controls. Patients were stratified by tumor regression grade scores. We analyzed mycobiome-immune marker correlations and developed multilayer perceptron (MLP) models using Boruta feature selection. Performance was validated in 37 independent pretreatment patients. Functional causality was confirmed using Candida_boidinii in syngeneic mouse experiments with anti-programmed cell death protein-1 (PD-1) therapy.

Results Patients with ESCC exhibited significant mycobiome dysbiosis compared with healthy controls, characterized by reduced alpha diversity and enrichment of pathogenic fungi including s_Rhodotorula_minuta, s_Actinomucor_elegans, and s_Candida_zeylanoides. Baseline mycobiome profiles distinguished treatment responders from non-responders before therapy initiation. Responders demonstrated higher fungal diversity, more stable co-occurrence networks, and enrichment of beneficial taxa (s_Candida_boidinii, g_Meyerozyma, s_Meyerozyma_guilliermondii, s_Trichosporon_dermatis) that correlated with Th1-polarized immunity and elevated cytotoxic markers (interferon-γ, interleukin (IL)-12p70, IL-2). Non-responders harbored immunosuppressive fungi (s_Candida_albicans, s_Candida_parapsilosis, s_Candida_glabrata, g_Saccharomyces) associated with Th2 skewing and regulatory cytokines (IL-4, IL-10, IL-13). Functional analysis revealed responders exhibited enhanced catabolic pathways and phospholipase activities, while non-responders showed upregulated nucleotide biosynthesis. The MLP model achieved robust discriminative performance (genus-level: training area under the receiver operating characteristic curve (AUC) 98.0%, test AUC 82.9%; species-level: training AUC 87.1%, test AUC 87.4%). Candida_boidinii administration enhanced anti-PD-1 efficacy in mice, validating predicted metabolomic and immune changes.

Conclusions Baseline gut mycobiome signatures predict NICT response in ESCC with high accuracy. Experimental validation confirms functional causality, enabling precision medicine approaches for patient stratification and identifying therapeutic targets.

Full Article: https://jitc.bmj.com/content/13/10/e011508

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Immunotoxicity and cancer risk exacerbation induced by tris(1,3-dichloro-2-propyl) phosphate exposure: insights from macrophage inflammatory responses and in vivo tumor models

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Abstract

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is widely detected in human tissues and associated with significant health risks. However, the immunotoxicity and health risk mechanisms of long-term TDCPP exposure remain poorly understood. This study integrates mRNA sequencing (mRNA-seq) and high-throughput cytokine profiling to elucidate key transcriptional and secretory changes associated with TDCPP-induced inflammatory responses. The findings underscore the potential health implications of TDCPP exposure, elucidating its inflammatory effects at the cellular level and in a breast cancer mouse model. TDCPP exposure led to significant secretion of TNF-α and other cytokines. mRNA-seq and cytokine analysis demonstrated that TDCPP activates the GSDMD/Caspase-8 pathway through TNF signaling, triggering cell death in THP-1 macrophages, resulting in an inflammation response, and aggravating tumor progression. RIPK1 serves as a pivotal regulatory factor in the TNF signaling pathway, playing a central role in modulating both cell death and inflammatory responses. In vivo studies using BALB/c mice showed that TDCPP enhanced cancer cell proliferation and promoted damage to liver and lung tissues. These results highlight the need for a more rigorous evaluation of the environmental and public health impacts of TDCPP and structurally related compounds, as TDCPP exposure may exacerbate health effects, particularly in vulnerable populations with weakened immunity or pre-existing conditions.

Immunotoxicity and cancer risk exacerbation induced by tris(1,3-dichloro-2-propyl) phosphate exposure: insights from macrophage inflammatory responses and in vivo tumor models Read More »

Protein iron transporters as potential therapeutic targets in cancer: A review

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Abstract

Iron is an essential trace element crucial for DNA synthesis, oxygen transport, and redox processes. In mammals, its homeostasis is strictly regulated by protein transporters like transferrin, solute carriers, and ATP-binding cassette proteins. They are specialized transmembrane proteins that facilitate iron uptake, export and intracellular trafficking. Dysregulation of these transporters can increase intracellular iron, boosting reactive oxygen species production and genetic instability, thereby promoting cancer hallmark processes such as sustained proliferation, apoptosis evasion, metastasis, and resistance to therapy. Transporters such as SLC11A2, SLC39A14, and ABCB7 notably modulate oncogenic pathways including JAK/STAT, TGF-β, Wnt, and HIF signaling. Such dysfunction reprograms cellular metabolism and signaling, contributing to cancer progression and therapeutic failure. Epigenetic modifications and polymorphisms in these transporters further enhance tumor aggressiveness and chemoresistance. Recent studies highlight the role of iron transporters in ferroptosis, an iron-dependent form of cell death, offering new therapeutic avenues. Targeting these transporters with small molecule inhibitors, microRNA therapies, and natural products has shown promise in preclinical models. This review explores the diverse roles of protein iron transporters in oncogenesis, emphasizing their potential as prognostic biomarkers and therapeutic targets.

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SNRPB/CCNB1 axis promotes hepatocellular carcinoma progression and cisplatin resistance through enhancing lipid metabolism reprogramming

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Abstract

Background

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality globally, significantly impacting worldwide health. Hence, identifying key molecular drivers of HCC progression is crucial for enhancing treatment options and prognostic methods. This study explores the function of Small Nuclear Ribonucleoprotein Polypeptides B and B1 (SNRPB) in HCC, unveiling critical pathways that affect the progression of the disease.

Methods

Utilizing multi-dimensional data that integrates bulk RNA sequencing (bulk RNA-seq), single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) from HCC patients, we have identified SNRPB as a pivotal gene associated with the spliceosome, playing a central role in both tumor initiation and progression. We also investigated the intricate process by which SNRPB influences cyclin B1 (CCNB1) expression through FOXM1-mediated activation, using a combination of bioinformatics, functional assays, Chromatin Immunoprecipitation (ChIP), and Co-Immunoprecipitation (Co-IP) studies. Complementary in vivo experiments and metabolic assays were conducted to explore the relationship between tumor growth and lipid metabolism further. Additionally, evaluations of cisplatin sensitivity were performed, providing an in-depth analysis of influence of SNRPB on HCC.

Results

Across multiple cohorts, SNRPB exhibited a marked upregulation within tumors, correlating significantly with poor prognosis. Knockdown of SNRPB suppressed HCC cell proliferation and migration, while promoting apoptosis. Mechanistically, SNRPB regulated CCNB1 expression via FOXM1-mediated transcription, and SNRPB overexpression enhanced lipid metabolism and cisplatin resistance. This increase in drug sensitivity was mediated through alterations in lipid metabolism and the regulatory effects on CCNB1, providing a comprehensive insight into multifaceted role of SNRPB in HCC pathology and potential therapeutic targets. Finally, CCNB1 knockdown reversed the proliferative and tumorigenic effects of SNRPB overexpression in a preclinical HCC model.

Conclusions

SNRPB promoted HCC progression by modulating the FOXM1-CCNB1 axis and lipid metabolism, and could act as a potential therapeutic target to augment chemotherapy sensitivity in HCC.

Full Article: https://jeccr.biomedcentral.com/articles/10.1186/s13046-025-03463-y

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Extracellular Vesicles Administered via Intrathecal Injection Mediate Safe Delivery of Nucleic Acids to the Central Nervous System for Gene Therapy

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ABSTRACT

Gene therapy holds great potential for treating neurological disorders, but its implementation is limited by the challenge of developing a safe and effective delivery method to the central nervous system (CNS). Red blood cell-derived extracellular vesicles (RBCEVs) have the potential to address these challenges due to their non-immunogenicity, non-cytotoxicity, ability to be redosed, and suitability for nucleic acid loading. In this study, we demonstrate the efficacy and safety of RBCEV-mediated nucleic acid delivery to the CNS. We found that RBCEVs administered through intrathecal injection are widely distributed across the CNS and efficiently taken up by neuronal cells. Delivery of RBCEVs loaded with GFP-encoding plasmids results in GFP expression in neurons. Our data also highlight the potential of RBCEVs to deliver plasmids encoding secretory proteins, resulting in protein secretion within the cerebrospinal fluid. Furthermore, experiments conducted in both mouse and non-human primate models indicate that intrathecal injection of plasmid-loaded RBCEVs do not lead to any systemic or local acute toxicity. In summary, our findings illustrate the potential of the RBCEV-based platform as a viable and safe approach for nucleic acid delivery to the CNS, facilitating further development of gene therapy for neurological disorders.

Full Article: https://isevjournals.onlinelibrary.wiley.com/doi/10.1002/jev2.70116

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EMT and cancer stem cells: Drivers of therapy resistance and promising therapeutic targets

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Abstract

Cancer continues to be a primary cause of death, resulting in substantial mortality and illness globally. It remains a significant global health issue, greatly affecting morbidity and mortality across the world. Therapeutic resistance poses a major challenge to cancer treatments, acting as a significant barrier to the effectiveness of both standard and targeted therapies. This resistance develops through various mechanisms that allow tumor cells to adapt to and escape the damaging effects of chemotherapy, radiation, and targeted therapies. Ultimately, this leads to disease recurrence and progression. This review examines the dual roles of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in promoting chemoresistance and metastasis. EMT is a dynamic and reversible biological process in which epithelial cells acquire mesenchymal characteristics, increasing their invasiveness and resistance to programmed cell death. CSCs are a subset of cancer cells with the ability to self-renew and play a crucial role in tumor relapse and resistance to treatment. EMT and CSCs are closely interconnected, collaboratively enhancing cancer cell plasticity, metastatic ability, and treatment resistance. The initiation of EMT in cancer cells can generate a CSC-like population, which promotes tumor recurrence and spread. This interaction highlights the importance of targeting both EMT and CSC pathways to develop more effective treatment strategies that address treatment resistance and prevent metastasis. Promising approaches include using natural substances, small molecules, and nanotechnology to block critical signaling pathways and interfere with resistance mechanisms. A more thorough understanding of the molecular factors underlying EMT and CSC plasticity is crucial for crafting personalized treatments that target tumor heterogeneity and improve clinical outcomes.

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Combination of KRAS ASO and RIG-I agonist in extracellular vesicles transforms the tumor microenvironment towards effective treatment of KRAS-dependent cancers

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Abstract

Rationale: Mutations in the KRAS gene drive many cancers, yet targeting KRAS mutants remains a challenge. Here, we address this hurdle by utilizing a nucleic acid-based therapeutic strategy delivered via extracellular vesicles (EVs) to simultaneously inhibit KRAS mutants and activate the RIG-I pathway, aiming to enhance anti-tumor immunity. Methods: Antisense oligonucleotides against KRAS mutants (KRAS ASOs) and RIG-I agonist immunomodulatory RNA (immRNA) were loaded into EVs and administered to KRAS-mutant cancer models. The therapeutic effects were assessed in colorectal and non-small cell lung cancer (NSCLC) tumor models, as well as patient-derived pancreatic cancer organoids. Immune responses were evaluated by analyzing tumor microenvironment’s changes, dendritic cell activation, and T cell memory formation. The treatment efficacy was evaluated based on the tumor development and overall survival. Results: The KRAS-ASO and immRNA combination treatment induced immunogenic tumor cell death and upregulated interferons in KRAS-dependent cancers. In a colorectal tumor model, the therapy shifted the tumor microenvironment to an immunogenic state, activated dendritic cells in sentinel lymph nodes, and promoted memory T cell formation. In an aggressive NSCLC model, the treatment resulted in a strong anti-tumor activity and extended survival without any adverse effects. Validation in patient-derived pancreatic cancer organoids confirmed the clinical translation potential of this approach. Conclusions: EV-mediated delivery of ASOs and immRNA effectively inhibits KRAS mutants and activates RIG-I, leading to a robust anti-tumor immune response. This strategy holds promise for effectively treating KRAS-driven cancers and improving clinical outcomes.

Combination of KRAS ASO and RIG-I agonist in extracellular vesicles transforms the tumor microenvironment towards effective treatment of KRAS-dependent cancers Read More »

The solute carrier family 11 transporters: a bridge between iron homeostasis and tumor biology

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Abstract

Iron is an essential trace element in the human body, and its imbalance is closely linked to the initiation and progression of various malignancies. The solute carrier family 11 (SLC11) transporters, comprising SLC11A1 and SLC11A2, play pivotal roles in iron metabolism and cellular homeostasis, processes intricately linked to oncogenesis. SLC11A1, primarily expressed in macrophages, modulates immune responses and reshapes the tumor microenvironment, while SLC11A2, a ubiquitous iron transporter, regulates dietary iron absorption and ferroptosis, an iron-dependent form of programmed cell death. Dysregulation of these transporters is associated with tumor initiation, progression, metastasis, and therapy resistance. In this review, we provide an overview of the physiological functions of SLC11 transporters in iron metabolism and their pathological roles in cancer biology. Emerging evidence highlights their involvement in key oncogenic pathways, including p53, JAK/STAT, Wnt and HIF signaling. Pharmacological and genetic interventions targeting SLC11 transporters have shown the potential to disrupt tumor progression and enhance treatment efficacy. By exploring the intricate roles of SLC11A1 and SLC11A2 in cancer progression, this review offers insights into their potential as biomarkers and therapeutic targets, paving the way for innovative cancer treatment strategies.

Full Article: https://doi.org/10.1186/s12964-025-02293-x

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