DNA Nanoclusters Combined with One‐Shot Radiotherapy Augment Cancer Immunotherapy Efficiency

Abstract

A key clinical strategy to improve cancer immunotherapy is to combine with radiotherapy (RT) to boost the abscopal effect, a phenomenon in RT where local tumor treatment induces systemic regression of metastatic lesions. [2][3][4] However, radiationinduced macrophage accumulation and infiltration in the irradiated tumor is one of the key factors for cancer recurrence and metastasis. Recognizing and killing the residual surviving cancer cells after RT by persistently and stably stimulating immune response is an effective strategy to prevent cancer recurrence and distant metastasis.Tumor with a high density of tumorassociated macrophages (TAMs) is characterized by a high mortality rate and poor prognosis with a high tendency of recurrence and metastasis. [5][6][7][8] RT is currently well considered as one of the most effective remedies for cancer. [9] Especially for one-shot irradiation at moderate doses, it is as effective in tumor cell killing as multifractionated treatment and has an even higher retreatment rate than multifractionated treatment with a relatively less toxic effect on the surrounding late-responding normal tissues. [10][11][12] At the same time, surviving cancer cells after single-dose irradiation had a stronger Immunotherapy shows immense promise for improving cancer treatment. Combining immunotherapy with radiotherapy provides a conspicuous advantage due to its enhanced abscopal effect. However, established immune tolerance mechanisms in the tumor microenvironment can hamper the generation of a sufficient abscopal effect. Herein, a type of DNA nanocluster (DNAnc) that is self-assembled by a CpG-ODNs-loaded Y-shaped doublestranded DNA vector based on the unique complementary base-pairing rules is designed. The unique structure of DNAnc makes it load more than ≈8125.5 ± 822.5 copies of CpG ODNs within one single nanostructure, which effectively increases resistance to nuclease degradation and elevates the efficiency of repolarizing macrophages to an M1-like phenotype. Mechanistic studies reveal that more DNAncs are endocytosed by macrophages in the cancer tissue and repolarized macrophages to elicit a robust abscopal effect with the accumulation of macrophages induced by radiotherapy, generating potent, long-term, and durable antitumor immunity for the inhibition of tumor metastasis and the prevention of tumor recurrence, which provides a novel strategy to boost cancer immunotherapy.

DNA nanotechnology-based nucleic acid delivery systems for bioimaging and disease treatment

“…Recently, Liu's group reported a programmable DNA nanocluster (DNAnc) through the self-assembly from Y-shaped DNA subunits of three ssDNAs containing CpG ODN fragments, one of which was modified by a lipid molecule, making DNAnc have amphiphilic properties. 136 In this design, approximately 8125.5 ± 822.5 CpG ODN copies were loaded into an individual nanostructure, which displayed satisfactory biological stability against nucleases in vivo and improved repolarization efficiency of TAMs to the M1 phenotype. After intravenous administration, DNAnc successfully inhibited neoplasm development, metastasis, and relapse after radiotherapy through the stimulation of immunogenic tumor cell death, triggering dendritic cell activation and enhancing T-cell-induced anti-tumor immunization, which offered a promising approach for promoting tumor immunotherapy (Fig.…”

Advancing nanotechnology for neoantigen-based cancer theranostics

“…They can significantly improve ICD of tumour cells by triggering DNA structure destruction to release numerous neoantigens. 23,25 The process can be induced by phototherapy/radiotherapy through ROS or hyperthermal production, 21,22,25,26,94–101 chemotherapy/chemodynamic therapy, and sonodynamic therapy. 30,102–105 Xie et al developed programmable cytosine-phosphate-guanine (CPG) DNA nanoclusters (DNAnc) for promoting ICD of tumour cells, thus releasing abundant tumour endogenous neoantigens.…”

“…30,102–105 Xie et al developed programmable cytosine-phosphate-guanine (CPG) DNA nanoclusters (DNAnc) for promoting ICD of tumour cells, thus releasing abundant tumour endogenous neoantigens. 94 In addition, nanomaterials can efficiently capture tumour neoantigens through hydrophobic interactions or due to the presence of different functional groups, such as maleimide, amino, and catechol. They facilitate the delivery of these neoantigens to APCs, 25,26,32 improve the cross-presentation of neoantigens, and enhance their uptake by DCs.…”

Dual‐Functional Artificial Peroxidases with Ferriporphyrin Centers for Amplifying Tumor Immunotherapies via Immunogenic Cell Death

“…[2,3] With the progress of recent years, immunotherapy has been proven to be beneficial in tackling tumor cells, especially in synergistic with various treatments. [4][5][6][7][8] However, immunotherapy must be based on immune responses of sufficient effects. [9] Therefore, the modulation of the immunosuppressive tumor microenvironment (TME) is essential.…”