Systematic co-delivery of dual agonists to enhance cancer immunotherapy
Xiangxia Li, Guiyuan Chen, Yangyi Wang, Lanhong Su, Bo Chen, Kecheng Wu, Yun Xing, Zechenxi Song, Ruike Dai, Tianxin Liu, Jiaao Zhao, Zhe Xie, Peijie Zhou, Xiaoping Xia, Yuanzeng Min
Abstract
In the tumor immunosuppressive microenvironment (TIME), antigen presenting cells (APCs) usually exhibit a tumor suppressor phenotype. Toll-like receptors (TLRs) agonists could reprogram M2-type macrophages to M1-type and stimulate dendritic cells (DCs) maturation. The combination of TLR7/8 and TLR9 agonists seems to have synergistic therapeutic efficacy. Here, we designed a lipid-coated mesoporous silica nanoparticle (MSNs@Lipo) for the co-delivery of TLR7/8 agonist resiquimod (R848) and TLR9 agonist CpG oligodeoxynucleotides (ODNs) (CpG@MSNs-R@L-M). R848 was firstly conjugated onto the nanoparticle via silane chemistry, which is acidic responsive drug release. Then, CpG was loaded onto the nanoparticle through the positive charge mainly from TLR7/8 agonist R848. Our in vitro experiments further indicated that both drugs have acid-responsive release properties and could be taken up by DCs and located on the endosomes of APCs. More importantly, CpG@MSNs-R@L-M could significantly improve the antitumor efficacy in B16F10 melanoma model. The mechanistic study demonstrated that CpG@MSNs-R@L-M could remarkably modulate the TIME by promoting the maturation of DCs and repolarizing macrophages from M2 to M1 phenotype and facilitating the infiltration of tumor cytotoxic T cells. It was concluded that in comparison to single agonist, the co-delivery of dual agonists, CpG and R848, can improve anti-tumor immune responses for cancer immunotherapy.