Construction of ionizable iron nanoadjuvants for personalized tumor vaccine treatment

Tumor vaccines represent a therapeutic method that can induce body-specific and persistent anti-tumor immune response, and have great prospects
for improving clinical tumor treatment.
However, the low immunogenicity of tumor antigens, low cytoplasmic delivery efficiency, and poor lymphoid organ targeting greatly limit the level of anti-tumor immune response induced by tumor vaccines, which in turn leads to poor
clinical treatment results.
The development of novel immune adjuvants provides a powerful strategy
to improve the efficacy of oncology vaccines.
As one of the most promising immune adjuvants, Stimulator of interferon genes (STING) signaling agonists stimulates the activation of STING signaling in antigen-presenting cells and induces the secretion of Type I interferon (IFN-I), thereby promoting the cross-presentation of tumor antigens and the proliferation and activation
of subsequent T lymphocytes 。 However, when free STING agonists participate in the design of tumor vaccines as immune adjuvants, there are still problems such as poor lymphoid organ delivery efficiency and inability to improve antigen cytosolic release, which is also one of the key reasons for the poor clinical treatment effect of the current water-soluble vaccine, that is, the physical mixture of
tumor antigen and immune adjuvant.
Therefore, the development of a new generation of vaccine preparations to synergistically promote the cytoplasmic delivery of tumor antigens and the efficient activation of STING signals in lymphoid organs is of great significance
for improving tumor vaccine treatment.

In response to the above challenges, the Navy Research Group published a research paper entitled "Acid-ionizable iron nanoadjuvant augments STING activation for personalized vaccination immunotherapy of cancer" in Advanced Materials on December 28, 2022.
In this study, a library of ionizable iron nanoadjuvants was innovatively constructed to specifically amplify the activation
of STING signals in draining lymph nodes.
At the same time, nano-adjuvants can universally and efficiently deliver multiple forms of tumor antigens and induce strong and specific anti-tumor immune responses
in vivo.
This study demonstrates the promise
of ionizable iron nanoadjuvant for personalized tumor vaccine treatment.

The researchers were the first to demonstrate that iron oxide nanoparticles (IONPs), a clinically approved imaging contrast agent, can induce IFN-I mass secretion
by inducing intracellular reactive oxygen species to synergistically stimulate STING signaling activation with the STING agonist MSA-2.
Subsequently, the researchers designed and synthesized a series of acid ionizable copolymers and self-assembled them with IONPs and MSA-2 to construct a library
of ionizable iron nanoadjuvants.
This nanoadjuvant efficiently drains and accumulates to lymph nodes, inducing significant expression of interferon-stimulating genes in lymph nodes
.
At the same time, the nano-adjuvant can be further used as a vaccine delivery vehicle to construct tumor nanovaccines
by self-assembly with the model antigen chicken egg albumin (OVA).
The nanovaccine can effectively promote the cytoplasmic delivery of antigens while activating STING signals in cascades, thereby achieving efficient antigen cross-presentation, and ultimately inducing a nearly 170-fold increase in antigen-specific CD8+ T lymphocyte responses, and showing significant tumor prevention and growth inhibition in
mouse B16OVA melanoma models.
In addition, the nanoadjuvant can also deliver autologous tumor cell membrane antigens obtained after surgical resection for postoperative tumor immunotherapy
.
The combination of nano-vaccine and immune checkpoint blocking therapy significantly inhibited the postoperative recurrence and distal metastasis of B16OVA and MC38 tumors, and induced long-term anti-tumor immune memory effects
.
In conclusion, ionizable iron nanoadjuvants represent a powerful and universal vaccine delivery platform, which can improve the efficiency of tumor antigen cross-presentation and T lymphocyte activation, and provide a new strategy
for personalized tumor vaccine treatment.

Fig.
1 Schematic diagram
of ionizable iron nanoadjuvant for personalized tumor vaccine treatment.

Chen Fangmin, a master's and doctoral student at the Shanghai Institute of Materia Medica, is the first author of the paper, and Yu Navy, a researcher at the Shanghai Institute of Materia Medica, is the corresponding author
of this paper.
Dr.
Li Tianliang provided key support
for the experimental design and technical route optimization of this paper.
Professor Luo Min of Fudan University, researcher Zuoquan Xie of Shanghai Institute of Materia Medica, Professor Zhiai Xu of East China Normal University and researcher Chunyong Ding of Shanghai Jiao Tong University gave strong support
to this project.
The research was supported
by the Key R&D Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, the International Cooperation Project of the Shanghai Municipal Science and Technology Commission, the Lingang Laboratory Open Fund, the Postdoctoral Fund, the Shanghai Super Postdoctoral Program, the State Key Laboratory of Polymer Physics and Chemistry Open Fund, and the Foreign Young Scholars Fund of the NSFC.
The biological effect evaluation part of this study was strongly supported
by the National Protein Science Research (Shanghai) Facility of Zhangjiang Laboratory.

Article link: https://doi.
org/10.
1002/adma.
202209910

(Contributed by: Yu Navy Research Group)