STING-activating layered double hydroxide nano-adjuvants for enhanced cancer immunotherapy

Abstract

Cancer vaccines represent a promising therapeutic strategy in oncology, yet their effectiveness is often hampered by suboptimal antigen targeting, insufficient induction of cellular immunity, and the immunosuppressive tumor microenvironment. Advanced delivery systems and potent adjuvants are needed to address these challenges, though a restricted range of adjuvants for human vaccines that are approved, and even fewer are capable of stimulating robust cellular immune response. In this work, we engineered a unique self-adjuvanted platform (MLDHs) by integrating STING agonists manganese into a layered double hydroxide nano-scaffold, encapsulating the model antigen ovalbumin (OVA). The MLDHs platform encompasses Mn-doped MgAl-LDH (MLMA) and Mn-doped MgFe-LDH (MLMF). Upon subcutaneous injection, OVA/MLDHs specifically accumulated within lymph nodes (LNs), where they were internalized by resident antigen-presenting cells. The endosomal degradation of MLDHs facilitated the cytoplasmic release of antigen and Mn²⁺, promoting cross-presentation and triggering the STING pathway, which in turn induced a potent cellular immune response against tumors. Notably, OVA/MLMF induced stronger M1 macrophage polarization and a more potent T-cell response within tumor-infiltrating lymphocytes compared to OVA/MLMA, leading to significant tumor regression in B16F10-OVA bearing mice with minimal adverse effects. Additionally, combining MLMF with the vascular disrupting agent Vadimezan disrupted the tumor's central region, typically resistant to immune cell infiltration, further extending survival in tumor-bearing mice. This innovative strategy may show great potential for improving cancer immunotherapy and offers hope for more effective treatments in the future.