Genetic Engineering of Dendritic Cells Using Partially Zwitterionic Dendrimer-Entrapped Gold Nanoparticles Boosts Efficient Tumor Immunotherapy

Abstract

Effective processing and cross-priming of tumor neoantigen by dendritic cells (DCs) to T cells for spontaneous immune response generation to effectively kill cancer cells remain challenging in cancer immunotherapy. Here, we report a general approach to genetically engineer DCs through silencing their YTHDF1 protein (an important reader protein responsible for RNA m6A methylation) expression via a dendrimeric non-viral vector to boost effective tumor immunotherapy. Poly­(amidoamine) dendrimers of generation 5 were partially decorated with mannose and 1,3-propanesultone and then entrapped with gold (Au) nanoparticles. The created dendrimer nanoplatform has an Au core size of 1.8 nm; possesses desired stability, good cytocompatibility, and excellent YTHDF1 siRNA compression ability; and enables targeted gene silencing of DCs overexpressing mannose receptors to upregulate the expression of CD80 and CD86, markers of DCs maturation, potentially leading to tumor antigen cross-presentation. With these properties owned, the combination of YTHDF1 silencing of DCs with programmed cell death-ligand 1 antibody can boost the best immunotherapy of a xenografted melanoma tumor model through the created antitumor immune responses. Findings in this study demonstrate a general approach of genetic engineering of DCs via a dendrimeric non-viral vector to effectively boost antitumor immunotherapy.

Roles and therapeutic implications of m6A modification in cancer immunotherapy

“…Several different inhibitors/activators have also been reported to exhibit anti-tumor effects. For example, STM2457 targeted key stem cell populations of AML to reverse the malignant phenotype of AML, revealing significant anti-leukemic effects (173). A synergistic anti-cancer effect through the combination of STM2457 and immunotherapy is looking forward to going into clinical trials.…”

Functionalized PAMAM constructed nanosystems for biomacromolecule delivery

“…An Au DENP nanoplatform modified with zwitterion and mannose were developed for the targeted gene silencing of dendritic cells to boost tumor immunotherapy. 163 Another Au DENP nanoplatform was partially modified with a hydroxyquinoline-2-carboxylic acid (8-HQC) on the periphery and chelated with Fe( iii ). The system produced reactive oxygen species under the tumor microenvironment (TME) and compacted plasmid DNA, thus achieving an Fe( iii )-induced Fenton reaction and gene therapy.…”

Advances in the Application of Nanomaterials to the Treatment of Melanoma

“…Accordingly, Ouyang et al constructed a zwitterion-mannose-modified Au DENP nanoplatform to target YTHDF1 gene-silencing DCs. In a mouse model of melanoma, the combination of this nano-delivery platform with PD-L1 was effective against immune-resistant tumors, tumor metastasis, and tumor recurrence [ 138 ]. Additionally, while DCs are composed of potent APCs that can be used to expand T cells for adoptive transfer and have shown some clinical success, expansion using DCs takes weeks or months to generate large numbers of tumor-specific cells.…”