A size-tunable nanoplatform: enhanced MMP2-activated chemo-photodynamic immunotherapy based on biodegradable...

Although immunotherapy is emerging as a revolutionary strategy for cancer therapy, its clinical effect is severely impaired by adaptive immune evasion and inefficient activation of antitumor immune response. Photodynamic therapy and chemotherapy have been shown to efficiently enhance the therapeutic effect of PD-L1 immunotherapy via different mechanisms. However, the lack of a precise drug delivery system seriously impedes the clinical application of combination therapy. To address these restrictions, a matrix metalloproteinases-2 (MMP2)-activated shrinkable nanosystem was developed to potentiate the antitumor efficacy of anti-PD-L1 antibody (aPDL1) delivered along with a chemo-photodynamic therapy. The nanosystem maintains its structure to accelerate tumor accumulation and shrinks down to a smaller size to facilitate tumor penetration and cellular uptake upon arriving in the tumor microenvironment. The exposure of aPDL1 on the surface of the biodegradable mesoporous silica cores (bMSNs) blocks the PD-1/PD-L1 interaction between tumor cells and T cells. Meanwhile, photosensitizer chlorin e6 (Ce6) and paclitaxel (PTX) loaded bMSNs effectively enter tumor cells and induce chemo-photodynamic therapy. The nanosystem elicits a chemo-photodynamic-induced immune response and improves the therapeutic effect of PD-L1 blockade mediated by aPDL1. Furthermore, the nanosystem displays a sustained prohibitive effect on tumor metastasis to distant sites. Our work presents a promising strategy for enhancing the efficacy of cancer immunotherapy.