Modulation of macrophage polarity with carboxymethyl chitin gated hollow mesoporous silica nanoparticles for elevating anti-tumor chemotherapy

The weak immunity of tumors after chemotherapy could cause tumor metastasis and progression. Therefore, to overcome the dilemma of obvious immune deficiency caused by chemotherapy, a nanosystem (N-IL-12/DOX/ alpha-TOS) consisted of thioketal (TK) bonds linked-hollow mesoporous silica nanoparticles (HMSNs) coated with carboxymethyl chitin (CMCH) by electrostatic interaction, and surface-functionalized glucose-regulated protein 78 binding peptide was prepared for loading doxorubicin (DOX), IL-12 and alpha-tocopheryl succinate (alpha-TOS). N-IL12/DOX/alpha-TOS displayed a mean size of 275 nm after encapsulated DOX, IL-12 and alpha-TOS with loading contents of 2.04 x 10-4, 4.01 x 10-2 and 7.12 x 10-2, respectively. The drug-free nanoparticles (NPs) showed good biocompatibility to both 4 T1 cells and RAW264.7 macrophages. N-IL-12/DOX/alpha-TOS could achieve localized release of IL-12, DOX and alpha-TOS by pH and H2O2 trigger in the tumor microenvironment (TME). Moreover, the combined therapy by N-IL-12/DOX/alpha-TOS remarkably elevated the anti-tumor therapeutic efficacy, enhanced immune responses via promoting tumor-associated macrophage (TAM) polarization into tumoricidal M1 phenotypes, and decreased lung metastasis with reduced side effects. N-IL-12/DOX/alpha-TOS exhibited as a promising strategy for combining chemotherapy and local macrophage modulation-immunotherapy for anti-tumor therapy.