Multifunctional Nanomodulators Regulate Multiple Pathways To Enhance Antitumor Immunity

Immunosuppression is a key factor leading to a low therapeutic efficiency of the currently used immunotherapies. Monotherapies are unable to overcome immunosuppression because of the complex interplay of immune cells in tumors. Herein, we report a multifunctional nanomodulator (MFNM) as a carrier to deliver different types of immune modulators for comodulating multiple pathways. An MFNM has a core-shell structure, in which small-molecule drugs are encapsulated in a mesoporous silica nanoparticle (MSN) core with a pHresponsive polymer layer. Further, the polymeric shell provides active sites that are readily modifiable by multiple types of antibodies to regulate the immune-related processes. By codelivering cyclophosphamide (CTX), aPDL1 (B7-H1), and a4-1BB (CD137L) monoclonal antibodies (mAbs) to tumors, an MFNM has been shown to regulate multiple immune pathways and enhance an antitumor immunity. As antibodies and small-molecule drugs loaded in an MFNM can be modified based on the tumor type, the MFNM provides a feasible platform for the development of advanced immunotherapies that require simultaneous modulation of multiple biological processes.