Nat Commun: Dong Yizhou's team developed biomimetic nanoparticles to deliver mRNA to enhance cancer immunotherapy

Antibodies against T cell co-stimulatory receptors have been developed to activate T cell immunity and are used in cancer immunotherapy
.

However, tumor-infiltrating immune cells often lack the expression of costimulatory molecules, which may hinder antibody-mediated immunotherapy

Cancer immunotherapy includes a variety of methods to stimulate the anti-tumor immune response, including cancer vaccines, cell-based therapy, immune checkpoint blocking, monoclonal antibodies, mRNA-based immunotherapy and nanoparticle-mediated immunotherapy
.

In particular, the use of immune checkpoint inhibitors has improved the overall survival rate of many cancer patients by targeting T cell co-suppression pathways (such as PD-1 and CTLA-4)

December 14, 2021, Ohio State University, Dong Yizhou in Nature Communications journal published a report entitled: Biomimetic nanoparticles The deliver mRNAs encoding costimulatory receptors and Enhance the Cell mediated T Cancer Immunotherapy research papers
.

Nature Communications Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy

The research team discovered that a phospholipid-derived nanoparticle, PL1, can effectively deliver mRNA to T cells in vivo and in vitro
.

In a variety of tumor models, the combined anti-tumor activity of PL1-OX40 mRNA and anti-OX40 antibody was significantly higher than that of anti-OX40 antibody alone

T cell-based cancer immunotherapy is a rapidly developing field
.

Recently, nanotechnology has been developed to improve T cell therapy, such as engineering T cells in vitro and regulating T cells in vivo

In this study, in order to explore nanoparticles that deliver mRNA to T cells, the research team designed and synthesized phospholipids and glycolipid derivatives (PLs and GLs), and used these materials to prepare biomimetic nanoparticles for mRNA delivery
.

PL1 nanoparticles can not only deliver co-stimulatory receptor mRNA to T cell lines in vitro, but also deliver co-stimulatory receptor mRNA to T cells in tumors in vivo, providing useful delivery materials for regulating T cell functions

Agonistic antibodies against costimulatory receptors can enhance anti-tumor T cell immunity and have been used in cancer treatment
.

For example, anti-OX40 antibodies can activate T cells, allowing them to eliminate tumor cells

In this study, PL1 nanoparticles were used to deliver OX40 mRNA to tumor-infiltrating T cells, increasing the expression of OX40, thereby enhancing the anti-tumor effect of anti-OX40 antibodies
.

In a variety of tumor models, PL1-OX40 and anti-OX40 combination therapy showed significant anti-tumor activity compared with a single antibody

Next, the research team continued to study the anti-tumor mechanism of this treatment in different tumor models
.

In order to further improve the anti-tumor activity of PL1-OX40 and anti-OX40 antibodies, the research team added anti-PD -1 and anti-CTLA-4 antibodies to the treatment plan

CD137 and OX40, members of the TNF receptor superfamily (TNFRSF), are co-stimulatory receptors expressed on T cells, which stimulate T cell proliferation and activate T cells when interacting with their cognate ligands
.
Some studies have reported that CD137 and OX40 are also expressed on dendritic cells.
These dendritic cells can bind to agonistic antibodies of dendritic cells, thereby enhancing dendritic cells to stimulate T cell proliferation and produce tumor antigen-specific CD8+ The ability of T cells to respond
.
In this study, PL1-OX40 nanoparticles induced the expression of OX40 on T cells and dendritic cells
.
Mechanism studies have shown that PL1-OX40 nanoparticles and agonist OX40 antibody directly stimulate T cells
.
At the same time, the program activates dendritic cells, which triggers subsequent stimulation of T cells
.

Finally, the research team found that their treatment strategy is compatible with multiple routes of administration
.
The combination therapy of PL1-OX40 and anti-OX40 antibody has significant anti-tumor activity
.
More importantly, in the lung metastasis model, systemic injection of anti-PD -1 + anti-CTLA -4 antibody and PL1-OX40 + anti-OX40 antibody reduced tumor metastasis
.
These results show that the treatment plan has a wide range of applicability in different treatment situations
.
At present, more and more costimulatory receptors have been widely studied for their mechanism of action, such as CD28 or CD27, GITR and ICOS27
.
The results of the research team laid a solid foundation for exploring more effective combined use of costimulatory receptors and agonistic antibodies for cancer immunotherapy
.

In summary, the research team proved that a phospholipid-derived nanoparticle, PL1, can effectively deliver MRNA to T cells in vivo and in vitro
.
In a variety of tumor models, the combined anti-tumor activity of PL1-OX40 mRNA and anti-OX40 antibody was significantly higher than that of anti-OX40 antibody alone
.
The treatment method significantly improves the immunotherapy effect of anti-PD -1 + anti-CTLA-4 antibody
.
Mechanism studies have shown that the delivery of PL1-OX40 mRNA can induce the activation of a variety of immune cells, including T cells and dendritic cells
.

 

Original source:

Original source:

Li, W.
, Zhang, X.
, Zhang, C.
et al.
Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy .
Nat Commun 12, 7264 (2021).
https://doi.
org/10.
1038 /s41467-021-27434-x.

Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy in this message