Dual delivery of immunostimulatory oligonucleotides and doxorubicin by magnetic nanoparticles and metal-organic frameworks for antitumor immunotherapy.

Abstract

The immunosuppressive tumor microenvironment (TME) remains a major challenge to effective cancer immunotherapy. We hypothesized that combining dendritic cell (DC) maturation with immunogenic cell death (ICD) could enhance antitumor immunity by simultaneously providing immune-activating signals and tumor-associated antigens. To achieve this, we developed a dual-nanocarrier utilizing distinct nanoparticles: surface-modified magnetic nanoparticles (MNPs) for CpG oligodeoxynucleotide (CpG ODN) delivery and metal-organic frameworks (MOFs) for doxorubicin (DOX) encapsulation. Separate carriers of the two agents enabled independent control of their delivery functions. CpG-pMNPs promoted DC maturation more effectively than an equivalent dose of free CpG ODN, whereas DOX@UiO-67 induced ICD. In breast tumor model, the combined treatment markedly suppressed tumor growth and prolonged survival. Immune profiling further showed increased matured DC in tumor-draining lymph nodes, enhanced tumor infiltration of T cells and cytotoxic T lymphocytes, and modulation of immunosuppressive immune populations. In the spleen, the combination treatment reduced regulatory T cells and increased the proportion of CD8⁺ effector memory T cells. Collectively, current research demonstrates that separate delivery of CpG ODN and DOX through optimized nanocarriers effectively remodels the local TME and improves therapeutic efficacy. This dual-carrier strategy provides a practical approach for combining therapeutic agents with contrasting physicochemical properties in cancer chemo-immunotherapy. STATEMENT OF SIGNIFICANCE: Cancer immunotherapy is often limited by an immunosuppressive tumor microenvironment (TME) that restricts effective immune activation. Chemo-immunotherapy combining CpG oligodeoxynucleotides (CpG ODN) with doxorubicin (DOX) may address this limitation by coupling dendritic cell (DC) maturation with immunogenic cell death in tumor. Here, we developed a dual-nanocarrier strategy in which CpG ODN and DOX were separately formulated in functionalized magnetic nanoparticles and metal-organic frameworks, respectively. This carrier-level separation enabled independent optimization of each therapeutic component while preserving their complementary functions within the tumor site. The combined treatment promoted DC maturation, remodeled the local TME, suppressed tumor growth, and prolonged survival in a murine breast cancer model. This work provides a practical method for combining physicochemically incompatible therapeutic agents in cancer chemo-immunotherapy.