Biodegradable nanoparticles-mediated targeted drug delivery achieves trans-spatial immunotherapy

Immunotherapy has been seriously retarded due to inadequate antigen presentation and a tumor cell-dominated immunosuppressive microenvironment (TME). Herein, biodegradable multifunctional mesoporous silica nanoparticles, with dispersed carbon nanodots incorporated into the frameworks, active TKD peptide modification on the surfaces and hydrophobic drug loading in the pores, were prepared for targeted chemotherapy synergized with trans-spatial immunotherapy. The nanoparticles were biodegradable due to nanodot-induced framework swelling, which would (1) kill the in situ tumor cells and promote antigen release by targeted chemotherapy and (2) trigger biodegraded debris involving TKD and CDs to largely adsorb the tumor antigens via π-π conjugation synergized hydrophobic interactions and then massively transport these antigens from the tumor cell-dominated TME to the immune cell-dominated spleen via TKD-mediated small size effects. Thereafter, these antigens can be processed into antigen peptides via TKD-mediated lysosome endocytosis and then activate T cells in the spleen via MHC complex construction and dendritic cell cytomembrane presentation. Therefore, improved immunotherapy with trans-spatial antigen presentation avoided TME immunosuppression, which when synergized with targeted chemotherapy, markedly enhanced the therapeutic outcomes of triple-negative breast cancer.