Immunosuppressive tumor microenvironment (ITM), poor immunogenicity, and low
tumor penetration markedly reduce the capability of
tumor immunotherapy. To address these challenges, we successfully engineered acidity-triggered nanoparticles (NPs) with size reduction and charge switchable features to boost
tumor immunotherapy based on
indoleamine 2,3-dioxygenase 1
siRNA (IDO1
siRNA) and immunogenic cell death (ICD). The NPs significantly augmented
tumor penetrating ability and improved cellular uptake via the detachment of
2,3-dimethylmaleic anhydride-grafted poly(
ethylene glycol)-poly(
L-lysine) copolymer (
mPEG-PLL-DMA, PLM) from large-sized NPs with a negative charge. Subsequently, the NPs with a positive charge and small size rapidly escaped from the lysosomes and released
mitoxantrone (MIT) and IDO1
siRNA. The antitumor immune response of IDO1
siRNA and MIT provided good antitumor capability by enhancing DC maturation, improving the number of CTLs, and downregulating the level of Tregs in
tumor tissues. In summary, the results demonstrated that charge-switchable NPs based on the blockage of the IDO1 pathway and ICD activation induce an efficient antitumor immune response, thus showing high potential for treating primary/distant
tumors and reducing
metastasis. STATEMENT OF SIGNIFICANCE: Acidity-triggered nanoparticles (NPs) with size reduction and charge reversal to boost
tumor immunotherapy based on
indoleamine 2,3-dioxygenase 1
siRNA (IDO1
siRNA) and immunogenic cell death (ICD) were engineered. NPs augmented
tumor penetrating ability and improved cellular uptake through the detachment of
mPEG-PLL-DMA (PLM) from the large-sized MIT/siR-PLM/PPA NPs with negative charge to expose miniature and positively charged MIT/siR-PPA NPs. The NPs rapidly escaped from the lysosome and sequentially released
mitoxantrone (MIT) and IDO1
siRNA. The antitumor synergistic effect of inhibiting the IDO1 pathway by IDO1
siRNA and inducing ICD by MIT provided good antitumor capability by enhancing DC maturation, improving the number of CTLs, and downregulating the level of Tregs in
tumor tissues. Thus, the NPs showed a promising pathway against aggressive and difficult-to-treat
cancers.