Sequentially responsive peptide assembling liposomes integrating photosensitizer and immune drug for enhanced photodynamic/immunotherapy in skin melanoma

Combining photodynamic therapy (PDT) and immunotherapy modalities has shown encouraging therapeutic efficacy against various metastasis cancers. Developing a functional nanoparticle for tumor-targeting and on-demand release of drug is still a major focus for advancing therapeutic approach. Herein, we assembled a β-cyclodextrin (β-CD) modified MMP-2 responsive peptide with a photosensitizer-loaded liposome to construct a tumor immune microenvironment and laser dual-triggered nano system (matrix metalloproteinase 2 (MMP-2) responsive peptide liposome, MR@Lip) for melanoma therapy. The β-CDs encapsulating SB-3CT were released due to the cleavage of the peptide substrate by MMP-2 which is highly expressed in tumor stroma. The localized released SB-3CT was kept in the stroma and inhibited the expression of MMP, down-regulating the soluble NKG2D ligands. The liposome loading photosensitizer Ce6 targeted and killed melanoma cells under laser irradiation, while induced the expression of NKG2D ligands and finally leading to an increase in sensitivity of A375 cells to NK cells. This study might provide novel insight into the development of a new nanomedicine to achieve programmed release of antitumor drugs and better integration of PDT and immune therapy for melanoma.