Nanotechnology has demonstrated tremendous clinical utility, with potential applications in
cancer immunotherapy. Although nanoparticles with intrinsic cytotoxicity are often considered unsuitable for clinical applications, such toxicity may be harnessed in the fight against
cancer. Nanoparticle-associated toxicity can induce acute necrotic cell death, releasing
tumor-associated
antigens which may be captured by antigen-presenting cells to initiate or amplify
tumor immunity. To test this hypothesis, cytotoxic cationic
silica nanoparticles (CSiNPs) were directly administered into B16F10
melanoma implanted in C57BL/6 mice. CSiNPs caused plasma membrane
rupture and oxidative stress of
tumor cells, inducing local
inflammation,
tumor cell death and the release of
tumor-associated
antigens. The CSiNPs were further complexed with bis-(3'-5')-cyclic dimeric
guanosine monophosphate (
c-di-GMP), a molecular adjuvant which activates the stimulator of
interferon genes (
STING) in antigen-presenting cells. Compared with unformulated
c-di-GMP, the delivery of
c-di-GMP with CSiNPs markedly prolonged its local retention within the tumor microenvironment and activated
tumor-infiltrating antigen-presenting cells. The combination of CSiNPs and a
STING agonist showed dramatically increased expansion of
antigen-specific CD8+ T cells, and potent
tumor growth inhibition in murine
melanoma. These results demonstrate that cationic nanoparticles can be used as an effective in situ
vaccine platform which simultaneously causes
tumor destruction and immune activation.