Salvianic Acid A-Loaded Layered Double Hydroxide Nanosheets Boost T-Cell Infiltration through Tumor Vascular Normalization for Enhanced Immunotherapy

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Abstract Abnormal tumor vasculature impedes T-cell migration and compromises immunotherapy. Conventional anti-angiogenic strategies fail to restore the endothelial barrier and adhesion molecules. This limitation hinders long-term therapeutic benefits. Therefore, simultaneously restoring vascular function and activating immunity is essential. Herein, a pH-responsive, salvianic acid A-loaded manganese-aluminum layered double hydroxide nanosystem (S-LDH) was developed for synergistic regulation. In the acidic tumor microenvironment, S-LDH degrades in situ to release salvianic acid A and manganese ions. Released salvianic acid A directly repairs endothelial junctions via the β-catenin/claudin-5 pathway, restoring vascular integrity to promote immune cell infiltration. Concurrently, released manganese ions induce oxidative stress and trigger ICD via Fenton-like reactions while amplifying the cGAS-STING pathway to promote dendritic cell maturation and cytotoxic T-cell responses. Furthermore, STING activation upregulates endothelial adhesion molecules, further facilitating T-cell infiltration. In a 4T1 murine breast cancer model, S-LDH increased CD8+ T-cell infiltration by 10.9-fold and CD4+ T-cell infiltration by 4.3-fold compared with free salvianic acid A, confirming that simultaneous vascular repair and immune activation overcome the endothelial barrier. This work establishes a strategy that repairs tumor endothelial integrity and upregulates adhesion molecules to overcome this limitation by enabling T-cell infiltration.

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