Mannose and Hyaluronic Acid Dual-Modified Iron Oxide Enhances Neoantigen-Based Peptide Vaccine Therapy by Polarizing Tumor-Associated Macrophages

SIMPLE SUMMARY: Cancer vaccine therapy is promising, though its efficacy is compromised in an immunosuppressive tumor microenvironment. Tumor-associated macrophages (TAMs) have the potential to be repolarized to an antitumor subtype, and their antigen-presenting ability might enhance the efficacy of cancer vaccination. Here, we aimed to develop a nanoparticle with adjuvant effect that could be a carrier for neoantigen-based vaccine to target and repolarize TAMs in situ. Therefore, we prepared a hyaluronic acid and mannose dual-modified iron oxide nanoparticle, and the enhanced efficiency of nanoparticle intake of macrophages was confirmed. It could repolarize macrophages and outperformed a commercialized iron oxide nanoparticle, ferumoxytol. Combined with peptides, this nanoparticle strongly inhibited TC1 tumor growth, and 40% of mice reached complete regression. This is the first report using mannose, hyaluronic acid, and iron oxide to target TAMs and achieve ideal outcomes in vivo. This study provides a facile nanoplatform for neoantigen-based vaccine therapy and a reference for repolarizing TAMs to promote immunotherapy. ABSTRACT: Neoantigen-based cancer vaccine therapy is a breakthrough in the field of immunotherapy. However, it is difficult for vaccines against neoantigens to overcome the immunosuppressive microenvironment, where tumor-associated macrophages (TAMs) play a significant role. Herein, we report an iron oxide nanoparticle modified with hyaluronic acid and mannose to reshape the tumor microenvironment by targeting and repolarizing TAMs from protumor M2 to antitumor M1 phenotype. Mannose decoration could confer the nanoparticle-enhanced TAM targeting ability, while hyaluronic acid and iron oxide could repolarize M2-like macrophages both in vitro and in vivo. Combined with antigenic peptides, this nanovaccine could significantly increase the infiltration of CD8(+) T cells into tumor tissue and strongly activate dendritic cells in sentinel lymph nodes. Finally, we used the dual-modified nanoparticles to first convert the tumor microenvironment and then the nanovaccine administration in a TC1 tumor model to further enhance efficacy. This strategy inhibited tumor growth and achieved a 40% cure rate in mice (two of five). In summary, this study provides a potent and rationally designed nanoadjuvant to enhance antitumor efficiency and facilitate delivery of neoantigen vaccines by repolarizing TAMs and harmonizing immune cells.