Xianguang Ding

Radiotherapy (RT) remains a cornerstone in cancer treatment, yet its immunogenic potential is not fully harnessed for personalized immunotherapy. Here, we report that extracellular vesicles released after radiotherapy (REVs) encapsulate tumor-specific antigens reflective of individual tumor profiles, thereby enabling them to serve as potential personalized antigen repositories. We found that REVs were enriched with immune-related proteins, particularly those involved in antigen processing and presentation. Leveraging this immunostimulatory capacity, we constructed a personalized antigen nanocarrier by surface-engineering these REVs with a thin iron hydroxide coating (REVs@FeOOH). This nanocarrier, which functions as a personalized cancer vaccine, efficiently disrupted the acidic endosomal environment in dendritic cells (DCs), promoting antigen escape into the cytosol and facilitating cross-presentation. Concurrently, the FeOOH layer catalyzed the generation of reactive oxygen species via a Fenton-like catalytic reaction, further driving DC maturation. REVs@FeOOH activated robust antitumor T cell responses and remodeled the immunosuppressive tumor microenvironment. This nanoengineering strategy provides a cost-effective and personalized platform for cancer immunotherapy, with translational potential in breast cancer and other solid tumors.

Current technologies for measuring cancer metabolism have limited clinical utility, as they require invasive tissue sampling and lack analytical versatility. Here, we report a programmable nanotechnology platform that directly profiles extracellular vesicles (EVs) in patient biofluids to comprehensively capture metabolic alterations within the tumour milieu. This technology, termed atomically configured catalytic hybrids for profiling extracellular vesicle metabolites (ACTIVE), employs dual-matched biotic–abiotic nanohybrids based on defect-engineered transition-metal dichalcogenide peroxidase to catalytically quantify EV-associated metabolites. Each hybrid comprises a biomimetic peroxidase grown in situ on a metabolite-responsive biological oxidase. By spatially and energetically aligning their redox centres to enable direct electron transfer, these hybrids establish efficient tandem catalytic cascades that detect low-abundance metabolites in complex samples, achieving >30-times-higher catalytic efficiency than wild-type catalysts. In EV profiling applications, ACTIVE enables measurements in native biofluids (>10³-fold improvement), captures a broad spectrum of metabolites (including their conversion dynamics) across EV subpopulations from diverse cellular systems and reflects dynamic changes in metabolic pathways during cellular reprogramming. In clinical specimens, using only 5 µl of native ascites fluid, ACTIVE reveals distinct metabolic reprogramming signatures within the tumour milieu, enabling stratification of patient prognosis.

Antigen presentation within solid tumours presents a significant clinical challenge for systemic immune activation. Although radiotherapy or chemotherapy can generate tumour antigens by destroying tumour cells, the insufficient number and impaired function of dendritic cells within solid tumours compromises effective antigen presentation. Here we present plant-derived nanoparticles coated with nanohydroxyapatite that promote dendritic cell activation and amplify the production of dendritic-cell-derived antigen-presenting vesicles in vivo through the modulation of intracellular immune conversion and calcium signalling. The technology, termed the intratumoural generation of immunopresentation vesicles after tumour exposure, enabled a dramatic enhancement in antigen presentation within lymph nodes and, consequently, boosted systemic immune response, exhibiting superior antitumour efficacy in multiple solid tumour models when combined with radiotherapy. This strategy of amplifying immunoreactive nanovesicle production in vivo may serve as a promising immunopotentiating platform, advancing various cancer treatments.

Extracellular vesicles (EVs) are promising biomarkers for liquid biopsy, but their clinical application is limited by intrinsic heterogeneity and the lack of methods capable of resolving functionally distinct EV subpopulations at the single-vesicle level. Conventional bulk analyses obscure rare but clinically relevant EV subsets, while most single-EV approaches focus on physical properties or surface markers, with limited access to intravesicular functional information. Here, we report a fusion-enabled EV detection strategy at the single-particle level for functional profiling of macrophage-derived EVs. Liposomal probes encapsulating L-arginine, NADPH, and a nitric oxide (NO)-responsive fluorescent dye are engineered to fuse with EV membranes, delivering substrates into the vesicle lumen. In macrophage-derived EVs, inducible nitric oxide synthase (iNOS) catalyzes NO production, activating the fluorescent probe and generating a localized signal within individual vesicles. Signal generation is confined to vesicle-restricted reactions, ensuring specificity and minimizing background. The formation of hybrid vesicles further facilitates optical detection using conventional fluorescence microscopy.

Extracellular vesicles (EVs) are emerging as promising circulating biomarkers for liquid biopsy due to their abundant molecular information, such as proteins, nucleic acids, and metabolites. However, the metabolic profiling of EVs remains largely unexplored, much less exploiting their intrinsic metabolic features for disease diagnosis. In this study, we demonstrate that the metabolic-related inducible nitric oxide synthase (iNOS) activity of macrophage-derived EVs serves as an effective biomarker for phenotypic profiling and further evaluating lung inflammation. By integrating a cascade amplification strategy that combines the biocatalysis of EV iNOS activity with the electrocatalysis of defective tungsten disulfide quantum dots (WS ₂ QDs), we develop an ACTIVITY (Amplified Cascade-catalysis TestIng for VesIcular meTabolic activitY) method for rapid assaying of metabolically active EVs. When applied to bronchoalveolar lavage fluid samples, this activity-based EV profiling differentiates pneumonia patients from healthy controls and further facilitates the monitoring of disease treatment, suggesting the potential of EV metabolic activity for diagnostics.

Tumor-derived extracellular vesicles (TEVs) are promising autologous cancer vaccines due to their intrinsic tumor-associated antigens. However, their trans

Immunotherapy has transformed cancer treatment by enabling the immune system to target tumors more precisely. However, challenges such as immunosuppression within the tumor microenvironment, off‐target effects, and limited success in treating solid tumors continue to hinder its broader effectiveness. Extracellular vesicles (EVs), secreted by various cell types, have drawn increasing interest for their potential to overcome these barriers. Tumor‐derived EVs can promote immune evasion but also carry tumor antigens that stimulate immune responses. Meanwhile, EVs from immune cells, such as dendritic cells and macrophages, can enhance immune function by delivering signaling molecules that support both innate and adaptive immunity. Advances in EV engineering have further improved their stability, targeting capabilities, and therapeutic potential. This review explores the dual roles of tumor‐derived and immune cell‐derived EVs in cancer immunotherapy, discusses recent progress in EV engineering that improves their clinical utility, and evaluates their potential to augment existing immunotherapies.