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

Abstract

Some chemotherapeutic agents, such as anthracyclines 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-α and IFN-γ 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.

DNA Nanomaterials‐Based Platforms for Cancer Immunotherapy

“…developed a similar DNA tetrahedron‐based vehicle loaded with doxorubicin and CpG motifs for synergetic therapy. [ 35 ] They verified that dying tumor cells after the in vitro treatment with doxorubicin‐loaded tetrahedral structures generated ICD signals including CRT, HMGB1 and ATP, which can activate DCs to stimulate the presentation of tumor antigens to T cells ( Figure A). Their functional DNA tetrahedron also elicited excellent immunological activation and antitumor effects in vivo, including cytotoxic T cell proliferation and antitumor cytokine TNF‐α and interferon‐γ (IFN‐γ) secretion.…”

“…Reproduced with permission. [ 35 ] Copyright 2022, American Chemical Society. B) tFNA structures integrated with CpG motifs and doxorubicin molecules (DFNAIA) for transdermal delivery‐based chemo‐immunotherapy for malignant melanoma treatment.…”

Dendrimer-like Hierarchical Framework Nucleic Acid for Real-Time Imaging of Intracellular Trafficking

“…Recent developments in framework nucleic acids (FNAs) have attracted wide attention. FNAs possess certain superior physicochemical characteristics such as high programmability, purity, and uniformity. − Moreover, FNAs can function as frameworks to organize nanoparticles as well as various molecular entities with the help of available chemical and biological modification strategies. − In the field of biomedical research, FNAs represent a unique type of drug carriers and cellular imaging probes due to their intrinsic biocompatibility and versatility. − In contrast to single- or double-stranded DNAs that can barely enter cells by themselves, self-assembled DNA nanostructures are capable of entering multiple cell lines. , Accordingly, FNAs with different shapes and sizes have been exploited in cell-based applications such as biosensing, , bioimaging, , immunostimulation, , and cancer therapy . For example, the anticancer drug doxorubicin (DOX) can attach to FNAs via intercalation into the DNA strands.…”

“…12,13 Accordingly, FNAs with different shapes and sizes have been exploited in cell-based applications such as biosensing, 14,15 bioimaging, 16,17 immunostimulation, 18,19 and cancer therapy. 20 For example, the anticancer drug doxorubicin (DOX) can attach to FNAs via intercalation into the DNA strands. FNA-mediated delivery facilitates specific recognition of tumor cells and circumvents DOX resistance in certain cancer cells.…”

Endoplasmic Reticulum-Targeting AIE Photosensitizers to Boost Immunogenic Cell Death for Immunotherapy of Bladder Carcinoma

“…Particularly, induction of immunogenic cell death (ICD) of tumor cells is an effective strategy to boost tumor antigen release, thereby enhancing tumor immunogenicity . ICD is a form of regulated cell death, and the cancer cells undergoing ICD can produce a large number of tumor-associated antigens and damage-associated molecular patterns (DAMPs), including surface-exposed CRT (ecto-CRT) and extracellularly released ATP, HSP70, and HMGB1. − Among these DAMPs, ecto-CRT acts as an “eat me” signal, attracting antigen-presenting cells, such as dendritic cells (DCs), to recognize and phagocytose the dying tumor cells . Simultaneously, the released ATP, HSP70, and HMGB1 play critical roles in promoting DC maturation and the presentation of tumor antigens to T cells. − As a result, ICD of tumor cells effectively initiates and augments the antitumor immunity, promoting massive infiltration of CD8+ T cells into the tumor microenvironment and transforming “cold” tumors with low immunogenicity into “hot” tumors with a positive immune response. − Therefore, during the treatment of bladder cancer, efficiently evoking the ICD of bladder cancer cells might exert a cancer vaccine-like effect to trigger strong antitumor immune responses and immune memory, offering a promising strategy for the eradication of bladder cancer.…”