A Bispecific Nanobridge Derived from Immunogenic Tumor Membranes Restores Dendritic Cell–T Cell Crosstalk for Enhanced Solid Tumor Immunotherapy

Abstract In solid tumors, communication between dendritic cells (DCs) and T cells is impaired by poor immune infiltration and lack of physical contact, limiting current immunotherapies. Here, we develop a bispecific immune-bridging platform (NVMB) to address these limitations. NVMB consists of tumor cell membrane-derived nanovesicles enriched with damage-associated molecular patterns (DAMPs) that activate DCs and support T-cell responses. The vesicle surface is further functionalized with two aptamers targeting DCs and CD8+ T cells, respectively, thereby enhancing their spatial proximity and facilitating functional DC–T cell interactions. This biomimetic design combines colloidal stability with programmable surface functionalization. Mechanistically, NVMB promotes DC–T interactions and enhances activation-associated phenotypes in both cell populations. In multiple immunocompetent mouse tumor models, NVMB suppresses tumor growth, increases intratumoral accumulation of mature DCs and activated CD8+ T cells, and reshapes the tumor microenvironment transcriptome toward enhanced antitumor immune responses. Moreover, combination with immune checkpoint blockade (ICB) further improves antitumor efficacy compared with either monotherapy, supporting the potential of NVMB as a complementary strategy for enhancing ICB responses. In patient-derived cocultures of circulating tumor cells (CTCs) and autologous peripheral blood mononuclear cells (PBMCs), NVMB enhances T-cell-mediated clearance of CTCs. These findings support NVMB as a stable and modular nanoplatform that integrates immunogenic signaling with immune-cell spatial coordination, providing a promising strategy for strengthening antitumor immunity and improving the efficacy of existing immunotherapies.