Lymph node-inspired immunoregulatory hydrogel with siRNA delivery property for postoperative glioblastoma treatment

Glioblastoma multiforme (GBM) is a refractory malignant tumor of the central nervous system; treating GBM remains challenging because many drugs cannot cross the blood–brain barrier (BBB). The presence of meningeal lymphatic vessels indicates significant potential for treating GBM with immunotherapy. However, limited immune cell numbers and immunosuppressive tumor microenvironment present additional challenges. Lymph nodes (LNs) play crucial roles in antitumor immunity, including roles in facilitating cellular interactions and lymphocyte expansion. Inspired by LN functions, we constructed an acid-responsive hydrogel to enhance local immune therapy efficacy. Local injection of this hydrogel into the tumor surgical cavity bypassed the BBB and reversed the adenosine-induced immunosuppressive tumor microenvironment by delivering small interfering RNA (siRNA) to knockdown ecto-5′-nucleotidase. Antigen release induced by doxorubicin, with imidazoquinoline, established a local inflammatory microenvironment to promote cellular interaction and lymphocyte expansion, significantly improving tumor clearance. Overall, this study presents a novel approach for GBM immunotherapy that is inspired by LN functions and demonstrates promising clinical translational value for future treatments.