Self-Assembled Immunostimulatory Tetrahedral Framework Nucleic Acid Vehicles for Tumor Chemo-immunotherapy

Some chemotherapeutic agents, such as anthracydines and oxaliplatin, can induce immunogenic cell death (ICD) with additional immune responses against cancer. However, ICD-based immunotherapy is limited by the nonspecific distribution of drugs and various side effects. Here, an immunostimulatory self-assembled tetrahedral framework nucleic acid (tFNA) vehicle was constructed to potentiate the chemo-immunotherapy, in which doxorubicin (DOX) acted as a chemotherapeutic agent and an ICD-inducer. Meanwhile, the immunostimulatory CpG-tFNA was employed as a nanocarrier to deliver DOX and an adjuvant to enhance the immunotherapy. Damage-associated molecular patterns (DAMPs) generated by DOX from dying tumor cells, such as calreticulin (CRT), high mobility group protein 1(HMGB1), and adenosine triphosphate (ATP), can activate dendritic cells (DCs) and trigger an immunological response. Afterward, CpG-tFNA with immunostimulatory properties works to boost the DOX-induced immunotherapy. Consequently, CpG-tFNA/DOX showed excellent antitumor effects and immunological activation, including CD8(+) T cell proliferation and antitumor cytokine TNF-alpha and IFN-gamma secretion. Moreover, chemo-immunotherapy can also be enhanced synergistically when coadministered with PD-L1. In conclusion, CpG-tFNA/DOX promotes the ICD-associated chemo-immunotherapy and strengthens the connection between traditional chemotherapy and immunotherapy, representing a novel strategy for clinical application. Moreover, the concept of ICD-related immunotherapy can also be extended to other treatments such as radiotherapy which can induce immunogenic cell death as well.

Automated summary

A self-assembled tetrahedral framework nucleic acid (tFNA) vehicle was developed to enhance the chemo-immunotherapy for cancer treatment. The tFNA delivered the chemotherapeutic agent doxorubicin (DOX) and an adjuvant CpG to potentiate immune responses, resulting in excellent antitumor effects and immunological activation. This novel strategy strengthens the connection between traditional chemotherapy and immunotherapy and can be extended to other treatments inducing immunogenic cell death.