A20-Luc and B16F10-OVA | Injectable Supramolecular Hydrogel for Co-Delivery of CAR-T Cells and IL-15 Breaks Through Bott
This study addresses the challenges of insufficient T cell infiltration and the immunosuppressive microenvironment in solid tumors for CAR-T cell therapy. Researcher developed an injectable supramolecular hydrogel based on hyaluronic acid-tert-butylphenylacetic acid (HA-TP) and acrylated β-cyclodextrin (AC-β-CD). This hydrogel forms a three-dimensional network through host-guest interactions and photocrosslinking, enabling the co-encapsulation and sustained release of CAR-T cells and IL-15. In melanoma and B-cell lymphoma models, the hydrogel significantly enhanced intratumoral T cell infiltration, activation, and the proportion of memory T cells, while reducing systemic inflammatory responses. The study validated the hydrogel's mechanical properties, biocompatibility, and therapeutic efficacy through rheology, electron microscopy, flow cytometry, and in vivo imaging, establishing a novel strategy for local delivery platforms in solid tumor immunotherapy. The findings were published on October 14, 2025, in Materials Today Bio.Core Findings:
· The hydrogel co-delivering CAR-T cells and IL-15 achieved a 95.1% tumor growth inhibition rate in a lymphoma model.· Intratumoral CD3+ T cell infiltration increased to 26.2%, with CD8+ T cells comprising 56.9%.
· Memory T cell (TCM/TEM) proportions significantly increased, while serum inflammatory cytokine levels decreased, indicating enhanced immunological memory and reduced systemic side effects.
Research Highlights:
· Shear-thinning and self-healing properties: Enable minimally invasive injection and in situ gelation, streamlining cell delivery.· Porous network structure: Allows controlled release of cells and cytokines, prolonging local retention time and improving bioavailability.
Innovative Breakthrough:
This study presents the first construction of a supramolecular hydrogel based on the HA-TP/AC-β-CD host-guest photo-crosslinking system for the synergistic delivery of CAR-T cells and IL-15, significantly enhancing the efficacy and safety of solid tumor immunotherapy.Graphical Abstracts & Key Data:
Figure 1: Hydrogel Characterization
Rheological tests, scanning electron microscopy, and cell viability assays compared three formulations (HA-CD₁.₉, HA-CD₂.₃, Gel-CD₁.₁). HA-CD₁.₉ exhibited the highest storage modulus and cytocompatibility, with a porous structure (pore size ~50 μm) supporting cell encapsulation and migration. Its shear-thinning and self-healing behavior makes it suitable for injectable delivery.
Figure 2: Enhanced Anti-tumor Efficacy via Peritumoral Injection of Hydrogel-Encapsulated OVA-Specific CD8+ T Cells and IL-15
In a B16F10-OVA melanoma model, peritumoral injection of hydrogel encapsulating OVA-specific CD8+ T cells and IL-15 (T + IL15@gel) significantly inhibited tumor growth, with the high-dose group showing >90% tumor volume reduction. The sustained release prolonged T cell activity without significant weight loss.
Figure 3: T Cell Phenotype Analysis Post-Treatment in Melanoma
Flow cytometry and immunofluorescence revealed that the T + IL15@gel group had significantly higher intratumoral CD3+ T cell infiltration, enhanced CD69+ activation marker expression, and increased proportions of central memory (TCM) and effector memory (TEM) T cells.
Figure 4: Hydrogel-Encapsulated CAR-T Cells and IL-15 Control A20-Luc B-cell Lymphoma Growth
In a B-cell lymphoma model, the CAR-T + IL15@gel group achieved 80.5% tumor growth inhibition, with the high-dose group reaching 95.1%. In vitro Transwell assays confirmed sustained CAR-T cell cytotoxicity, and bioluminescence imaging verified significant tumor reduction.
Figure 5: Enhanced Intratumoral T Cell Infiltration and Activation Post-Hydrogel Treatment
Flow cytometry confirmed significantly increased intratumoral CD3+ and CD8+ T cell populations, alongside elevated CD69+ activated cells in the CAR-T + IL15@gel group.
Figure 6: Memory T Cell Phenotype and Safety Assessment in Lymphoma
Post-treatment, the CAR-T + IL15@gel group showed higher TCM and TEM proportions in peripheral blood and tumors, with decreased serum inflammatory cytokines (IL-1β, TNF-α, IFN-γ, GM-CSF), indicating enhanced memory response and reduced systemic side effects.
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