Protein corona-driven nanovaccines improve antigen intracellular release and immunotherapy efficacy


Cancer immunotherapy makes use of the patient’s existing immune system to eradicate the tumor, stop its growth, or increase the patient’s chance of survival. Tremendous advancement in immunotherapy technologies have been achieved recently. A new technology named tumor vaccines which is using tumor antigens “proteins overexpressed in tumors or uniquely expressed polypeptides” to trigger the immune system and an anticancer immune response. However, when employed alone, it is challenging to adequately elicit the immune response due to the low immunogenicity of the majority of tumor antigens. As a result, adding the right adjuvants is required to boost the immune response. However, the free antigen and adjuvant molecules are readily destroyed and cannot be co-delivered to antigen presentation cells (APCs), inhibiting their synergistic enhancing effect. As a result, a mixture of antigens and adjuvants cannot induce an optimal immune response. The vaccine carrier dynamically binds to the surrounding proteins or bio-macromolecules during vaccine distribution in vivo, forming a protein corona layer that controls the vaccination’s physiological and therapeutic effects. A strong immune response is elicited by vaccine carriers, which are an essential component of vaccine composition. The interaction between the vaccine carriers and the intricate physiological fluids must be taken into account in order to increase the efficacy of vaccine distribution, in addition to the rational design of the composition, shape, and size of vaccine carriers. Although the protein corona effect’s significance in medication delivery is widely acknowledged, knowledge of the practical application of the protein corona to enhance antigen controlled release is still lacking.

In a recent study published in the Journal of Controlled Release, Yiqun Du, Hongzhong Zhou, Ganglin Su, Mengdan Ma, and Professor Yuchen Liu from Shenzhen Institute of Translational Medicine and Shenzhen Institute of Synthetic Biology in China developed a protein corona-driven nanovaccine (PCNV), which has the double impacts of resisting protein corona-induced antigen extracellular secretion and helping to promote protein corona-triggered antigen cytosolic release under reductive circumstances. In order to retain the antigen’s good stability before entering the APC, they chemically linked the antigen protein with the nucleic acid molecule CpG by taking advantage of the fluorine effect during the assembly process of fluorinated carriers and nucleic acids. The authors designed a smart disulfide link between the antigen and CpG that could be cleaved by a high concentration of GSH within the cells to effectively release the antigen from APCs.

The research team developed a PCNV in order to co-deliver the antigen and the adjuvant CpG and achieve antigen controlled antigen intracellular release. In particular, the fluorinated dendrigraft-poly-lysine and cleavable antigen-CpG conjugate were assembled to create the nanovaccine. The extracellular stability of the cleavable antigen-CpG conjugate and the potent assembly ability of fluorinated DGL prevented the antigen from dissociating from the carrier under the protein corona effect prior to the internalization of the nanovaccine by APCs. The intracellular reduction environment caused the antigen and CpG to dissolve their covalent connections once the nanovaccine had penetrated the APCs, and when combined with the intracellular protein corona, this caused a controlled release of antigen within the cell. Furthermore, the newly designed nanovaccine’s escaped endosomal degradation which enhanced antigen cross-presentation. When the authors compared their PCNV formulation to the other antigen-involved formulations, they demonstrated that PCNV triggered high IgG production and a CD8+ T cell immunological response indicating its superior efficacy. They further tested their formulation in mice and showed that PCNV significantly improved the preventive and therapeutic antitumor response.

According to the authors it is possible to boost the effectiveness of antigen intracellular release and elicit an antigen-specific immune response by adjusting the protein corona effect and intracellular lowering circumstances. As a result, the rational application of the protein corona effect offers an efficient method for administering vaccines. The new formulation design can be versatile tool to deliver a high amount of antigen plus adjuvant(s) in a targeted manner to APC.

About the author

Prof. Yuchen Liu is mainly engaged in the identification and intervention of cancer cells using synthetic biological approaches. He has published papers in many famous journals such as Nature Methods, Nature Communications (3 papers), Genome Biology, Cell Discovery, Biomaterials, Theranostics (2 papers) and eLife. He was one of the “GEN Top 10 Under 40 professionals” in biopharma research and has been selected into the “Forbes 30 Under 30 Asia list” in Healthcare & Science.

About the author

Yiqun Du received his Ph.D. in 2020 at the School of Biotechnology, Jiangnan University. Then he worked as a postdoctoral fellow at the Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital. In 2022, he moved to the School of Tea and Food Science and Technology, Anhui Agricultural University as a professor. His research interests focus on the nanovaccine construction, rational design of drug delivery system, and synthetic biology.


Du Y, Zhou H, Su G, Ma M, Liu Y. Protein corona-driven nanovaccines improve antigen intracellular release and immunotherapy efficacy. Journal of Controlled Release. 2022 May 1;345:601-9.

Go To Journal of Controlled Release.