Ren He/Nie Guangjun/Zhao Xiao developed a hydrogel platform loaded with RNA-liposome nanoparticle drugs for the treatment of postoperative recurrence of pancreatic cancer

Pancreatic cancer is a highly malignant digestive system tumor, and traditional methods such as surgery and chemotherapy in clinical treatment have a very limited prolongation of the life cycle of pancreatic cancer patients, and increase the toxic reaction
of patients to drugs.
In recent years, the development of tumor immunotherapy technology has opened up a new way and method
to improve the prognosis of pancreatic cancer patients.

However, in the pancreatic tumor immune microenvironment, most immune cells are in a state of imbalance between number and function, which is usually manifested as active and abundant tumor-associated macrophages (TAMs) with immunosuppressive effects.
However, the number of CD4+, CD8+ effector T cells, NK cells and DC cells with antitumor effects is reduced, and the phenotype and state
are non-functional or immature.
Moreover, in the metastasis and recurrence of pancreatic cancer, the number of TAMs of M2 phenotype (promoting tumorigenesis) increased significantly, which is an important indicator
of poor prognosis.

Therefore, targeting TAMs in the pancreatic cancer microenvironment to improve the response rate of immunotherapy and reduce the systemic toxicity of immunotherapy is expected to become one of the effective immunotherapy strategies to solve the recurrence of
pancreatic cancer after surgery.

Immunomodulatory factor 5 (IRF5) plays an important regulatory role in the polarization of macrophages, which can repolarize M2 TAMs into M1 TAMs (inhibit tumorigenesis), thereby preventing tumorigenesis and metastasis
.
In addition, chemokine ligand 5 (CCL5) is a class of cytokines that regulate normal T cell expression and secretion, and CCL5/CCR5 interactions may promote tumorigenesis in a variety of ways, stimulate angiogenesis, modulate extracellular matrix, induce supplementation of stromal cells and inflammatory cells, and participate in immune escape mechanisms
.
Therefore, increasing the expression of IRF5 in the tumor microenvironment and reducing the expression of CCL5 promote the polarization of M1 TAMs, increase CD8+ T cell infiltration, reshape the tumor immune microenvironment, and help reduce the occurrence and metastasis
of pancreatic cancer.

Recently, Professor Ren He's research group of the Affiliated Hospital of Qingdao University and the research group of Nie Guangjun and Zhao Xiao of the National Nanoscience Center cooperated to publish a paper in the journal Nano Letters entitled "Injectable immunotherapeutic hydrogel containing RNA-loaded lipid nanoparticles reshapes tumor microenvironment for" Pancreatic Cancer Therapy research paper, which was also selected as the cover paper
of the current issue.

The study developed an in situ injectable sustained-release hydrogel platform loaded with RNA-liposome nanoparticle (LNP) drugs for the study
of postoperative recurrence of pancreatic cancer.

Professor Ren He's research group has long been committed to basic and clinical translational research of pancreatic cancer, and has confirmed in a series of research works that FOXP3 is expressed in the nucleus of pancreatic cancer epithelial cells, and as a functionally conserved transcription factor, it induces the infiltration of Tregs in pancreatic cancer tissues by promoting the transcription of chemokine CCL5, inhibits the activity of CD8+ killer T cells (Oncogene, 2017), and defines pancreatic epithelial cells with both epithelial and immune characteristics as regulatory epithelial cells
。 In preclinical experiments, the combination of anti-PD-L1 and CCL-5 achieved significant tumor suppression effect in the treatment of pancreatic cancer with upregulated tumor FOXP3 expression, which may solve the current situation of poor response to single anti-immune checkpoint therapy (STTT, 2020).

Based on the previous research of Professor Ren He's team, this work constructs a chitosan hydrogel platform loaded with IRF5 mRNA and CCL5 siRNA nanoparticles, which has many advantages
such as temperature sensitivity, injection line, degradation, controlled release, and immunity.
Among them, RNA (such as mRNA, siRNA) is used as a gene delivery molecule, carrying genetic information, guiding protein synthesis, up-regulating or down-regulating the translation efficiency of proteins, and solving the problem of "undruggable" proteins
.
It realizes the controllable release of RNA drugs, up-regulates IRF5 and down-regulates CCL5, promotes the transformation of M2 tumor-associated macrophages to M1 type, thereby enhancing the infiltration of CD8+ T cells, reshaping the tumor immune microenvironment, and effectively inhibiting the recurrence of pancreatic tumors after surgery, which has important guiding significance
for the clinical treatment of pancreatic cancer.

The research work was carried out
in cooperation with the Affiliated Hospital of Qingdao University and the National Center for Nanoscience.
Gao Chao, a postdoctoral fellow at the Affiliated Hospital of Qingdao University, is the first author of this paper, and Professor Ren He, Nie Guangjun Research Institute and researcher Zhao Xiao are the common correspondents
of this paper.