Programmable prodrug micelle with size-shrinkage and charge-reversal for chemotherapy-improved IDO immunotherapy

IDO blockade-based immunotherapy has been impeded by the activation of antitumor immune response and low delivery efficiency of immunotherapeutic, resulting from natural biological barriers and immune resistance. Herein, a programmable drug delivery nanosystem with enhanced tumor penetration and endocytosis is constructed for chemotherapy-enhanced immunotherapy by loading immune checkpoint IDO inhibitor NLG919 in pH/redox cascade-responsive prodrug micelle. The nanosystem shrinked micelles sizes and converted charge from negative to positive for enhanced tumor penetration and endocytosis in responding to the weakly acidic tumor microenvironment. The endocytosed nanosystem dramatically disassembled and released curcumin and NLG919 in redox-rich cytoplasm. In vitro and in vivo studies demonstrate that the nanosystem not only effectively overcame biological barriers, but also significantly boosted antitumor immune response and reduced immune resistance. It was realized by the combined effects of chemotherapy-enhanced immunogenicity, and NLG919-induced IDO-blockade immunotherapy, consequently inhibiting tumor growth, metastasis and recurrence with high efficiency in vivo. The study offers a nanoplatform with deep tumor penetration, high cellular uptake and effective antitumor immune response for the advance of chemo-immunotherapy.