A research team led by Yuan Zhen, head of the Centre for Cognitive and Brain Sciences (CCBS) and professor in the Faculty of Health Sciences (FHS) at the University of Macau (UM), has achieved a significant milestone in the precision intervention of brain disorders. The team has developed a novel ferritin-based photoimmunotherapeutic in situ vaccine (FIT), offering a promising solution for treating lethal brain malignancies, including glioblastoma (GBM) and brain metastases (BM). These findings have been published in Cell Biomaterials, a sister journal of Cell, garnering widespread attention for their innovative application in biomedicine and brain science.

Glioblastoma and brain metastases remain among the most formidable challenges in modern medicine. Their high mortality rate is primarily attributed to the blood-brain barrier (BBB), which restricts the infiltration of most therapeutic agents and immune cells into brain tissue. While conventional treatments such as surgery, chemotherapy, and radiotherapy can provide temporary relief, they often fail to induce a sustained anti-tumor immune response, leading to high recurrence rates. Consequently, there is an urgent need for novel therapies that can bypass anatomical barriers and activate systemic immunity.

Figure 1. DC-guided Trojan horse photoimmunotherapy for brain tumor. First, the ferritin-based Trojan horse in situ vaccine is internalized by dendritic cells, activating them and facilitating their homing to lymph nodes. Subsequently, these activated DCs migrate to the brain tumor site, effectively acting as “Trojan horse” to deliver the vaccine into the tumor. Upon NIR laser ablation, tumor cells undergo pyroptosis, triggering the release and drainage of tumor antigens to the deep cervical lymph nodes (dCLNs). This process primes antigen-presenting cells (APCs), ultimately amplifying systemic immunity and leading to significant tumor regression.

To address this bottleneck, the research team engineered a dual-drug-loaded ferritin nanocage vaccine (FIT). This vaccine leverages human heavy-chain ferritin (HFn) as a carrier, encapsulating a potent immune agonist (T785) within its core and adsorbing a photosensitizer, indocyanine green (ICG), on its surface. The hallmark of this therapy lies in its “Trojan Horse” delivery mechanism. Administered via subcutaneous injection in the neck, the FIT vaccine precisely targets the draining deep cervical lymph nodes (dCLNs), where it is recognized and internalized by dendritic cells (DCs). These activated immune cells act as “Trojan Horses,” transporting the therapeutic cargo along the natural pathways of the meningeal lymphatic vessels (MLVs) directly into the intracranial tumor. Upon exposure to near-infrared (NIR) light, the vaccine triggers localized photothermal and photodynamic effects, which ablate tumor cells and release tumor-associated antigens, subsequently igniting a robust and lasting systemic anti-tumor immune cascade. In orthotopic mouse models of GBM and BM, the FIT vaccine demonstrated exceptional efficacy, achieving long-term survival in over 50% of the experimental group without observable neurotoxicity. This strategy not only achieves precise intracranial drug delivery but also successfully remodels the immunosuppressive tumor microenvironment.

Figure 2. A pH-responsive ferritin-based photoimmunotherapeutic in situ vaccine primes antitumor immunity. (A) FIT was engineered by loading the TLR7/8 agonist T785 into the HFn nanocage using a disassembly/reassembly method, followed by surface adsorption of the NIR photosensitizer ICG. (B) In orthotopic brain tumor models, FIT drains to CLNs, activating DCs, priming T cells, and stimulating cytokine release. After escaping from acidic endo-lysosomal compartments, the encapsulated T785 was released from the core, and FIT reassembles into a 24-mer ferritin structure with ICG adsorbed on the surface. FIT is then transported to the brain via MLVs (green pathways), carried by activated dendritic cells, where NIR irradiation induces localized photothermal and photodynamic effects, triggering pyroptotic tumor cell death and antigen release. These antigens drain to dCLNs, further amplifying APC activation and systemic anti-tumor immunity, including robust CNS-directed responses.

Figure. 3 Characterization and evaluation of FIT as a dendritic cell-mediated Trojan horse nanoplatform for targeted brain tumor therapy. (A) Time-lapse confocal imaging of DC2.4 cells illustrating the intracellular trafficking of FIT during the first 12 h post-incubation (scale bar = 5 μm). FIT predominantly localizes to endo-lysosomes at 1-3 h, begins to accumulate in the cytoplasm after 6 h, and fully escapes by 12 h, consistent with pH-triggered disassembly/reassembly-mediated endo-lysosomal escape. Schematic illustrates the proposed pH-responsive disassembly/reassembly mechanism within pre-DCs. (B) Confocal images showing colocalization of BODIPY-labeled ferritin (HFnBD) and ICG within the cytoplasm after intracellular processing (scale bar = 10 μm). Merged channels indicate that a fraction of ICG remains absorbed after cellular trafficking. (C) FLIM-FRET analysis of BODIPY-labeled ferritin (HFnBD) before and after coincubation with Cy5-labeled ferritin (HFnCy5) demonstrates a significant reduction in donor fluorescence lifetime following FIT internalization, confirming ferritin disassembly in the acidic endo-endo-lysosome and reassembly in the neutral cytoplasm (scale bar = 10 μm). (D) Quantification of FIT fluorescence at the injection site and in the brain following subcutaneous administration of FIT-loaded BMDCs. Although strong fluorescence was detected locally at the injection site, brain-associated fluorescence remained markedly lower throughout the observation period. This contrast indicates that only a small fraction of FIT-loaded dendritic cells can migrate from the peripheral injection site to the brain. (E) In vivo biodistribution following subcutaneous co-administration of Cy5-labeled BMDCs and FIT. At 5 min and 6 h, FIT-loaded BMDCs show strong accumulation at the cervical region and continue migrating toward the brain by 24 h.

This research represents a major breakthrough in the precision treatment of brain diseases by utilizing natural immune cell migration pathways. It provides new insights for the clinical translation of brain tumor therapies and paves the way for drug delivery in other central nervous system disorders.

Professor Zhen Yuan is the corresponding authors of the study. PhD students Shengnan Zhang, Keli An, and Siyi Lan are the co-first authors. The project was supported by several research grants, including those from the Science and Technology Development Fund of Macao SAR (FDCT 0014/2024/RIB1), the University of Macau (MYRG2022-00054-FHS，MYRG-GRG2023-00038-FHS-UMDF，MYRG-GRG2024-00259-FHS ), and the National Natural Science Foundation of China (NSFC).

The full text of the research article is available at:

https://www.cell.com/cell-biomaterials/abstract/S3050-5623(26)00029-2