Microenvironment-activatable cascaded responsive carbonized polymer dots as a theranostic platform for precise rapamycin delivery to potentiate the synergy of chemotherapy and γδ T cells-mediated immunotherapy against tumor

Abstract

The combination of chemotherapy and immunotherapy (also known as chemo/immunotherapy) promoted by nanomedicine has the potential to enhance the therapeutic effect in more patient populations. However, it is still affected by the inactivation of immune cells induced by traditional chemotherapy, which greatly impairs the synergistic effect of chemotherapy/immunotherapy substantially. Moreover, once tumor cells lose their MHC expression, the current popular CD8+ T cell-based immunotherapy may fail consequently. Herein, rapamycin, as mTOR signaling inhibitor associated with serious side effect once systemically administered, was incorporated into shell-core theranostic nanoplatform to augment synergy of chemotherapy and γδ T cell-mediated MHC-unrestricted immunotherapy against tumor without toxicity on γδ T cells. This nano-platform assembled from a cleavable shell and a carbonized polymer dot core can achieve accurate delivery of rapamycin with traceable imaging and cascade response. Such cascaded responsiveness has endowed it with improved blood compatibility, effective tumor accumulation, microenvironment-selective endocytosis, and hierarchical drug release facilitated by microenvironment-triggered programmable properties (size shrinkage, charge conversion and degradability) transition responding to blood-tissue-cells multi-level biological barriers. In vitro and in vivo experiments have shown that the nanoplatform not only promotes tumor chemotherapy by down-regulating mTOR signals, but also enhances γδ T cell-mediated immunotherapy by promoting the NKG2D pathway in a microenvironment-selective manner. In addition, the TCR-δ knockout mouse model was used to verify the synergy of chemical/immunotherapy promoted by the nanoplatform. In addition to multifunctional integrated therapeutic and diagnostic strategies, we also provide a paradigm to enhance the synergistic effect of chemotherapy/immunotherapy, and broaden the horizons of immunotherapy through γδ T cell-mediated replacement therapy assisted by nano-drugs.