Journal
SCIENCE ADVANCES
Volume 6, Issue 3, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aax5032
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Funding
- Ministry of Science and Technology [MOST 105-2628-E-007-007-MY3, 108-2321-B-009-004, 108-2221-E-007-104-MY5, MOST 107-3017-F-007-002, MOST 108-3017-F-007-003]
- Chang Gung Memorial Hospital-National Tsing Hua University Joint Research Grant [104N2744E1, 108Q2508E1, CORPG3I0071]
- National Health Research Institutes [NHRI-EX108-10609BC]
- Frontier Research Center on Fundamental and Applied Sciences of Matters from the Featured Areas Research Center Program [MOE 107QR001I5, 108QR001I5]
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While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)-cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2-encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8(+) T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.
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