A newly developed hydrogel platform loaded with RNA-liposome nanoparticle drugs for the treatment of

Pancreatic cancer is a highly malignant tumor of the digestive system, and traditional clinical treatments such as surgery and chemotherapy are very limited in terms of prolonging the survival cycle of pancreatic cancer patients and increasing toxic reactions to drugs. The advancement of tumor immunotherapy technology in recent years has created a new avenue and method for improving the prognosis of pancreatic cancer patients.

However, in the immune microenvironment of pancreatic tumors, most immune cells are numerically and functionally imbalanced, as evidenced by active function and the presence of tumor-associated macrophages (TAMs) with immunosuppressive effects. CD4+ and CD8+ effector T cells, NK cells, and DC cells with anti-tumor effects, on the other hand, were reduced in number and exhibited a non-functional or immature phenotype and status. Furthermore, the number of TAMs with the M2 phenotype (promoting tumorigenesis) increased significantly during pancreatic cancer metastasis and recurrence, which is an important indicator of poor prognosis.

Therefore, targeting TAMs in the pancreatic cancer microenvironment to improve the response rate and reduce the systemic toxicity of immunotherapy is expected to be one of the effective immunotherapeutic strategies to address postoperative recurrence of pancreatic cancer.

Recently, Prof. Ren He's group at the Affiliated Hospital of Qingdao University and the research group of Guangjun Nie and Xiao Zhao at the National Center for Nanoscience have published a paper in Nano Letters titled "Injectable immunotherapeutic hydrogel containing RNA-loaded lipid nanoparticles reshapes tumor microenvironment for pancreatic cancer therapy". The paper was also selected as the cover paper of the issue.

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

Professor Ren He's group has long been dedicated to basic and clinical translational pancreatic cancer research. FOXP3 is expressed in the nucleus of pancreatic cancer epithelial cells, induces Tregs infiltration in pancreatic cancer tissues by promoting the transcription of chemokine CCL5 as a functionally conserved transcription factor, inhibits CD8+ killer T cell activity, and defines pancreatic epithelial cells with both epithelial and immune characteristics as pancreatic epithelial cells were defined as regulatory-like cells. In preclinical trials, the combination of anti-PD-L1 and CCL-5 demonstrated significant oncogenic effects in the treatment of pancreatic cancer with upregulated tumor FOXP3 expression, which may explain the poor response to single anti-immune checkpoint therapy.

This work is based on the previous research of Prof. Ren He's team to build a chitosan hydrogel platform loaded with IRF5 mRNA and CCL5 siRNA nanoparticles, which has many advantages such as temperature sensitivity, injectability, degradability, controlled release, and immunity. Among them, RNA (such as mRNA and siRNA), as a gene delivery molecule, carries genetic information, directs protein synthesis, up-regulates or down-regulates the translation efficiency of proteins, and solves the problem of "non-druggable" proteins. The controlled release of RNA drugs, up-regulation of IRF5, and down-regulation of CCL5, promote the transformation of M2 tumor-associated macrophages to M1 type, enhance the infiltration of CD8+ T cells, reshape the tumor immune microenvironment, and effectively inhibit the recurrence of pancreatic tumors after surgery, which is of great significance for the clinical treatment of pancreatic cancer.

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