Manganese-Doped Silica-Based Nanoparticles Promote the Efficacy of Antigen-Specific Immunotherapy

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Abstract
Prophylactic human papillomavirus (HPV) vaccines are commercially available for prevention of infection with cancerogenic HPV genotypes but are not able to combat pre-existing HPV-associated disease. In this study, we designed a nanomaterial-based therapeutic HPV vaccine, comprising manganese (Mn4+)-doped silica nanoparticles (Mn4+-SNPs) and the viral neoantigen peptide GF001 derived from the HPV16 E7 oncoprotein. We show in mice that Mn4+-SNPs act as self-adjuvants by activating the inflammatory signaling pathway via generation of reactive oxygen species, resulting in immune cell recruitment to the immunization site and dendritic cell maturation. Mn4+-SNPs further serve as Ag carriers by facilitating endo/lysosomal escape via depletion of protons in acidic endocytic compartments and subsequent Ag delivery to the cytosol for cross-presentation. The Mn4+-SNPs+GF001 nanovaccine induced strong E7-specific CD8+ T cell responses, leading to remission of established murine HPV16 E7-expressing solid TC-1 tumors and E7-expressing transgenic skin grafts. This vaccine construct offers a simple and general strategy for therapeutic HPV and potentially other cancer vaccines. Key Points Mn delivered by silica-based nanoparticles conveys ROS-associated adjuvancy. Nanoadjuvant drives DC activation and Ag cross-presentation. Nanoadjuvant induces tumor-eliminating cytotoxic cellular immune response in vivo.
Funding Information
  • National Health and Medical Research Council (APP1124265)
  • University of Queensland Early Career Research Grant
  • Foundation Research Excellence Award
  • Queensland Biomedical Assistance Fund (2017003021)

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