Sulfonium-Driven Neoantigen-Released DNA Nanodevice as a Precise Vaccine for Tumor Immunotherapy and Prevention

Abstract

Peptide-based neoantigen vaccines hold tremendous potential for personalized tumor immunotherapy. However, effective delivery and controllable release of antigen peptides remain major challenges in stimulating robust and sustained immune responses. Programmable DNA nanodevices provide accurate fixed positions for antigens, which are convenient for the calculation of clinical dosage, and hold great potential as precise carriers. Here, a peptide–nucleic acid conjugate was prepared, which was driven by a propargyl sulfonium-based efficient and reversible bio-orthogonal reaction under weakly alkaline conditions, and folded into regular DNA nanodevice vaccines. The well-defined nanoplatform not only exhibits outstanding stability in serum, satisfactory safety, and effective internalization by antigen-presenting cells (RAW264.7 and BMDCs) but also obviously enhances cytokine (TNF-α, IL-6, and IL-12) secretion for further immune response. In vivo, the nanovaccine cooperating with OVA model antigens and CpG adjuvants stimulated an antigen-specific CD8+T cell response, significantly preventing the lung metastases of melanoma. In the B16-OVA tumor-bearing model, the growth inhibition rate of melanoma reached up to 50%. Similarly, the DNA nanodevice with neoantigen induced up to a maximum degree of complete MC-38 tumor regression in 80% of mice, possibly owing to antigen peptide reversible release driven by sulfonium and further cross-presentation. In brief, this study demonstrates that DNA nanodevices with sulfonium centers can provide a precise, biocompatible, and effective co-delivery vaccine platform for tumor immunotherapy and prevention.

DNA Nanomaterials‐Based Platforms for Cancer Immunotherapy

“…[ 113 ] As previously reported, DNA nanovaccines have been administrated subcutaneously, resulting in migration to lymph nodes and persistence for extended periods. [ 76,114 ]…”

“…[113] As previously reported, DNA nanovaccines have been administrated subcutaneously, resulting in migration to lymph nodes and persistence for extended periods. [76,114] The potential immunogenicity of DNA nanoplatforms is another concern that should also be intensely examined. When distributed systemically in vivo, DNA origami structures elicited modest proinflammatory immune responses that diminished over time.…”

Immunotherapy: cancer immunotherapy and its combination with nanomaterials and other therapies

“…134 In recent years, the formation of a self-assembling, self-assisting peptide delivery system by coupling tumor antigens to self-assembling peptides or constructing self-assembling peptide amphiphiles is a more advanced method for producing peptide vaccines. 135 Zhang et al 136 prepared a peptide-nucleic acid adduct that was powered by an efficient reversible bioorthogonal reaction of propargyl sulfonyl groups in weakly basic conditions and assembled into a conventional DNA nanodevice vaccine (Fig. 10).…”

Erythrocyte membrane-camouflaged DNA-functionalized upconversion nanoparticles for tumor-targeted chemotherapy and immunotherapy

“…19 The negatively charged CpG ODNs fail to penetrate the cell membrane and are easily digested by exonucleases in the serum or cytoplasm. 20 In recent years, lanthanide-based upconversion nanoparticles (UCNPs) have come into focus due to their distinctive chemical and optical properties. 21 According to research, UCNPs that carry and protect single-stranded DNA have been employed in cancer treatment and bioimaging.…”