Simultaneous innate immunity activation and immunosuppression improvement by biodegradable nanoplatform for boosting antitumor chemo-immunotherapy

The suppressive immune microenvironment and the accompanying insufficient immune activation limit the effectiveness of chemotherapy. Here we constructed a nanoplatform (CA-1@HMnO₂/HA-P-mAb) that can simultaneously activate innate immunity and relieve the immunosuppression to enhance the effect of immune-chemotherapy. The responsive cleavage of peptides (P) in the microenvironment established the basis for the separated and differentiated delivery to tumor cells and regulatory T cells (Tregs). The dropped antibodies (mAb) ran to Tregs to realize the efficacious remission of immunosuppression. Hollow mesoporous manganese dioxide nanoparticles (HMnO₂ NPs) coated with hyaluronic acid (HA) could achieve tumor targeting and rapid glutathione-responsive degradation in tumor cells. Interestingly, benefiting from the collapse of the HMnO₂ NPs, the large supply of curcumin analogue (CA-1) not only induced the apoptosis of cancer cells, but also improved their immunogenicity. Meanwhile, the released manganese could increase the production of inflammatory factors such as type I interferon by activating the stimulator of interferon genes pathway. The pro-inflammatory dominance and enhanced tumor immunogenicity resulting from the factors above, which further led to the maturation of dendritic cells (DCs) and the recruitment of cytotoxic T cells. CA-1@HMnO₂/HA-P-mAb NPs completed the remodeling of the tumor immune microenvironment and had satisfactory anti-tumor effect on tumor-bearing mice. Therefore, this novel platform may offer therapeutic potential for cancer chemo-immunotherapy.