RNA-based cancer vaccines are designed to translate tumor-associated antigens into antigen-expressing cells with the goal of stimulating CD4 + and CD8 + T cells to eliminate or reduce tumor burden. There are several barriers to the success of RNA vaccines, including sexual instability and low cell uptake of mRNA in conjunction with the need for targeted delivery to specific immunosuppressive neoplasms. Technologies that help protect RNA vaccines from shrinking them and delivering them to the right tissues are crucial to advancing these therapies.
Researchers have tried to use nanoparticles to deliver mRNA to target glands, but they only last one to two days after the injection – there is not enough time to trigger a complete immune response up. On the other hand, hydrogel has been used for the long-term release of encapsulated therapeutic agents. The agent can be released from the hydrogel through the density or contamination gradient of the hydrogel.
While this solves one problem of release, there is still a question about reducing the RNA vaccine before it can enter antigen-expressing cells. The inclusion of an adjuvant, such as a tax-like receptor agonist (TLR), in RNA vaccines can help stimulate the immune system and initiate textured and altered immune responses.
Using this blending strategy, researchers from the National Center for Neonatology and Technology in China designed an in situ transformative hydrogel containing RNA and adjuvant vaccines for cancer immunotherapy. They used graphene oxide, which has a large surface area, translating to high efficiency for drug loading.
The researchers selected resiquimod (R848), a TLR7 / 8 hydrophobic agonist, as the acknowledged coding mRNA and ovalbumin (mOVA) as a model mRNA vaccine. The mOVA was bonded to low molecular weight polyethylenimine (LPEI). Eventually, graphene oxide and LPEI were mixed and fabricated by electrostatic interactions to capture R848 and mOVA inside an injectable hydrogel.
In determining the formation of nanoparticles within the hydrogel, the researchers noted that the in vitro drug release of both the vaccine and the RNA vaccine was similar, suggesting that the circulating together in nanoparticles. In addition, the researchers examined the stability of mOVA within the hydrogel nanoparticles and found that encapsulated mOVA remained stable in the gel even after 10 days.
The in vitro data showed that the hydrogel nanoparticles were taken up by cells through endocytosis. The expression of ovalbumin protein in antigen-expressing cells was determined by a western blot and an enzyme-linked immunosorbent assay (ELISA).
The experts noted that the sensitivity of the protein was improved when the adjuvant was introduced into the formulation, possibly as a result of enhanced cellular delivery. Significant antigen presentation of the ovalbumin peptide on a major histocompatibility complex class was observed in treated dendritic cells, demonstrating successful expression of antigen.
Long-term release of RNA-adjuvant vaccine hydrogel was studied by injecting the substance into mice subcutaneously with the aim of delivering nanoparticles to the lymph nodes. The researchers confirmed that some of the mOVA was still trapped in the hydrogel 30 days after the injection.
The amounts of mOVA were steadily reduced over the 30 days. By analyzing the lymph nodes after the injection, the team confirmed that the nanoparticles were delivered to the lymph nodes with little spread to other major organs.
In mouse melanoma models, the researchers showed that the hydrogel hydrogel nanoparticles vaccinated with RNA inhibited tumor growth. Additional mOVA formulation had the highest therapeutic efficacy, which the authors suggested may be due to improved antigen presentation integration, targeted lymph node delivery, and long-term resolution potential.
The in vivo results also showed a significant increase in CD8 + T cells, cellular immune response signals, and tumor necrosis factor-alpha (TNF-α) among treated mice. RNA-adjuvant nanoparticles also induced high levels of ovalbumin-specific antibodies, suggesting that the hydrogel may also inhibit tumor recurrence or the formation of metastasis.
Overall, the results show that the hydrogel has great potential to achieve lasting and effective cancer immunotherapy with just one treatment.
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