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Novel bionic inspired nanosystem construction for precise delivery of mRNA.

ABSTRACT: The intracellular delivery of messenger (m)RNA holds great potential for the discovery and development of vaccines and therapeutics. Yet, in many applications, a major obstacle to clinical translation of mRNA therapy is the lack of efficient strategy to precisely deliver RNA sequence to liver tissues and cells. In this study, we synthesized virus-like mesoporous silica (V-SiO₂) nanoparticles for effectively deliver the therapeutic RNA. Then, the cationic polymer polyethylenimine (PEI) was included for the further silica surface modification (V-SiO₂-P). Negatively charged mRNA motifs were successfully linked on the surface of V-SiO₂ through electrostatic interactions with PEI (m@V-SiO₂-P). Finally, the supported lipid bilayer (LB) was completely wrapped on the bionic inspired surface of the nanoparticles (m@V-SiO₂-P/LB). Importantly, we found that, compared with traditional liposomes with mRNA loading (m@LNPs), the V-SiO₂-P/LB bionic-like morphology effectively enhanced mRNA delivery effect to hepatocytes both in vitro and in vivo, and PEI modification concurrently promoted mRNA binding and intracellular lysosomal escape. Furthermore, m@V-SiO₂-P increased the blood circulation time (t_1/2 = 7 h) to be much longer than that of the m@LNPs (4.2 h). Understanding intracellular delivery mediated by the V-SiO₂-P/LB nanosystem will inspire the next-generation of highly efficient and effective mRNA therapies. In addition, the nanosystem can also be applied to the oral cavity, forehead, face and other orthotopic injections.

SUBMITTER: Yang T

PROVIDER: S-EPMC10018395 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Novel bionic inspired nanosystem construction for precise delivery of mRNA.

Yang Taihua T Xia Lei L Li Gen G Zhao Jie J Li Jie J Ge Jiahao J Yuan Qinggong Q Zhang Jianjun J He Kang K Xia Qiang Q

Frontiers in bioengineering and biotechnology 20230302

The intracellular delivery of messenger (m)RNA holds great potential for the discovery and development of vaccines and therapeutics. Yet, in many applications, a major obstacle to clinical translation of mRNA therapy is the lack of efficient strategy to precisely deliver RNA sequence to liver tissues and cells. In this study, we synthesized virus-like mesoporous silica (V-SiO<sub>2</sub>) nanoparticles for effectively deliver the therapeutic RNA. Then, the cationic polymer polyethylenimine (PEI) ...[more]

PMID: 36937761

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Project description:Lytic cell death, such as pyroptosis, can trigger antitumour immune response. However, cancerous cells avoid lytic cell death by various escape mechanisms acquired through evolution. Moreover, persistent uncontrolled lytic cell death may inversely cause hyperactive immune response or T-cell exhaustion. Therefore, an oncolytic system capable of breaking through natural restrictions to dissolve cancer cells in a catalytic and controllable manner is needed. Here, we established a microscale cytotoxic T-cell-inspired oncolytic system (TIOs) by which the NIR light-generated reactive oxygen species could precisely rupture the plasma membrane of cancer cells by direct lipids peroxidation. Similar as cytotoxic T cells, TIOs present antigen-based cell recognition and catalytic cell-lysis ability; thus, the TIOs can trigger significant oncolysis and immune response in vivo. The TIOs exhibited exceptional tumour targeting and penetration without any inflammatory risk. We applied TIOs to antitumour therapies, which showed kinds of tumour models could be cleared efficiently with negligible injuries to major organs. Tumour regression was correlated with oncolysis-mediated inflammation and T-cell-based antitumor immune response. Owing to the tuneability of TIOs-mediated oncolysis, we further revealed that though the T-cell recruitment was comparable, the high-intense oncolysis induced acute inflammation in initial stage was crucial for potent antitumour immunity and immune memory effects, and low-intense oncolysis resulted in T-cell exhaustion and tumour progression. To the mice received low-intense oncolysis, although synergizing with anti-PD-1 therapies or STING activation rescued the immune dysfunction, STING activation released a more powerful boost to durative antitumour immunity by reshaping the stemness of CD8+ T cells. Our study provides new insights to design the oncolytic systems for antitumour immunity. Moreover, our application suggests that the intensity of initial inflammation plays a decisive role in maintaining oncolysis-induced antitumour immune function and STING activation holds promise for reversal of immune dysfunction due to T-cell exhaustion.

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Novel bionic inspired nanosystem construction for precise delivery of mRNA.

Publications

Novel bionic inspired nanosystem construction for precise delivery of mRNA.

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