Ivan S. Pires, Gil Covarrubias, Victoria F. Gomerdinger, Coralie M. Backlund, Eduardo Nombera Bueno, Margaret M. Billingsley, Mae L. Pryor, Apoorv Shanker, Ezra Gordon, Shengwei Wu, Andrew Pickering, Mariane B. Melo, Heikyung Suh, Darrell J. Irvine, Paula T. Hammond
Immunotherapies such as immune checkpoint inhibitors are effective in treating several advanced cancers, but these treatments have had limited success in metastatic ovarian cancer. Here we engineered liposomal nanoparticles carrying a poly-ʟ-arginine/poly-ʟ-glutamate coating that promotes their binding and retention on the surface of ovarian cancer cells. Covalent anchoring of the potent immunostimulatory cytokine interleukin-12 (IL-12) to phospholipid headgroups of the liposome core enabled the polymer-coated particles to concentrate IL-12 in disseminated ovarian cancer tumours following intraperitoneal administration. Shedding of the layer-by-layer coating and serum-protein-mediated extraction of IL-12-conjugated lipids from the liposomal core over time enabled IL-12 to disseminate in the tumour bed following rapid nanoparticle localization in tumour nodules. Optimized IL-12-polymer-coated nanoparticles promoted robust T cell accumulation in ascites and tumours in mouse models, extending survival compared with free IL-12 and sensitizing tumours to immune checkpoint inhibitors, eliciting strong immune responses and immune memory. Overall, these findings support the potential of these polymer-coated nanoparticles for the sustained delivery of IL-12 to disseminated metastatic ovarian cancer.