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Unzippable Siamese Nanoparticles for Programmed Two-Stage Cancer Immunotherapy
Mei Long1, Yanfeng Zhou1, Daoxia Guo1
1School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Abstract:
Epigenetic drugs (epi-drugs) can destruct cancer cells and initiate both innate and adaptive immunity, yet they have achieved very limited success in solid tumors so far, partly attributing to their concurrent induction of the myeloid-derived suppressor cell (MDSC) population. Here, dissociable Siamese nanoparticles (SIANPs) are developed for tumor cell-targeted delivery of epi-drug CM-272 and MDSC-targeted delivery of small molecule inhibitor Ibrutinib. The SIANPs are assembled via interparticle DNA annealing and detached via tumor microenvironment-triggered strand separation. Such binary regulation induces endogenous retrovirus expression and immunogenic cell death in tumor cells while restraining the immunosuppressive effects of MDSCs, and synergistically promotes dendritic cell maturation and CD8+ T cell activation for tumor inhibition. Significantly, immune microenvironment remodeling via SIANPs further overcomes tumor resistance to immune checkpoint blockade therapy. This study represents a two-pronged approach for orchestrating immune responses, and paves a new way for employing epi-drugs in cancer immunotherapy.
Insights
Novel Siamese nanoparticles deliver epigenetic drugs and an inhibitor to solid tumors, enhancing anti-tumor immunity and overcoming resistance to immunotherapy by targeting both cancer cells and myeloid-derived suppressor cells.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
- Drug Delivery
Background:
- Epigenetic drugs (epi-drugs) show promise in cancer therapy by inducing cell death and immune responses.
- Limited success in solid tumors is partly due to the induction of immunosuppressive myeloid-derived suppressor cells (MDSCs).
Purpose of the Study:
- To develop a targeted nanoparticle system for dual delivery of an epi-drug and an MDSC inhibitor.
- To overcome the immunosuppressive tumor microenvironment and enhance anti-tumor immunity.
Main Methods:
- Development of dissociable Siamese nanoparticles (SIANPs) for targeted delivery.
- Assembly of SIANPs via DNA annealing and triggered detachment in the tumor microenvironment.
- Co-delivery of epi-drug CM-272 to tumor cells and Ibrutinib to MDSCs.
Main Results:
- SIANPs induced immunogenic cell death in tumor cells and restrained MDSC immunosuppression.
- Enhanced dendritic cell maturation and CD8+ T cell activation were observed.
- The approach overcame resistance to immune checkpoint blockade therapy.
Conclusions:
- Dissociable nanoparticles offer a dual-targeting strategy for cancer immunotherapy.
- This approach enhances anti-tumor immunity and overcomes resistance to existing therapies.
- Paves a new way for employing epi-drugs in cancer immunotherapy.
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