MMP-2 Inhibitor-Mediated Tumor Microenvironment Regulation Using a Sequentially Released Bio-Nanosystem for Enhanced Cancer Photo-Immunotherapy

Abstract

Combining photodynamic therapy (PDT) with natural killer (NK) cell-based immunotherapy has shown great potential against cancers, but the shedding of NK group 2, member D ligands (NKG2DLs) on tumor cells inhibited NK cell activation in the tumor microenvironment. Herein, we assembled microenvironment-/light-responsive bio-nanosystems (MLRNs) consisting of SB-3CT-containing β-cyclodextrins (β-CDs) and photosensitizer-loaded liposomes, in which SB-3CT was considered to remodel the tumor microenvironment. β-CDs and liposomes were linked by metalloproteinase 2 (MMP-2) responsive peptides, enabling sequential release of SB-3CT and chlorin e6 triggered by the MMP-2-abundant tumor microenvironment and 660 nm laser irradiation, respectively. Released SB-3CT blocked tumor immune escape by antagonizing MMP-2 and promoting the NKG2D/NKG2DL pathway, while liposomes were taken up by tumor cells for PDT. MLRNmediated photo-immunotherapy significantly induced melanoma cell cytotoxicity (83.31%), inhibited tumor growth (relative tumor proliferation rate: 1.13% of that of normal saline) in the xenografted tumor model, and enhanced tumor-infiltrating NK cell (148 times) and NKG2DL expression (9.55 and 16.52 times for MICA and ULBP-1, respectively), achieving a synergistic effect. This study not only provided a simple insight into the development of new nanomedicine for programed release of antitumor drugs and better integration of PDT and immunotherapy but also a novel modality for clinical NK cell-mediated immunotherapy against melanoma.

Anti‐HER2 scFv‐nCytc‐Modified Lipid‐Encapsulated Oxygen Nanobubbles Prepared with Bulk Nanobubble Water for Inducing Apoptosis and Improving Photodynamic Therapy

“…The combination of PDT with PS‐loaded nano‐carriers was reported as a smart strategy to realize the spatiotemporally controlled release of loaded drugs, including fusion protein and PS. [ 47 ] Pro@Lipo‐PS‐NBs‐O 2 combined with PDT was found to be PS separated from the lipid carriers after NIR irradiation, which is complementary to experiments reported in the literature, [ 47 ] the released free PS would be aggregated in an aqueous solution. Due to the migration of PS from the inside to the outside of the carrier, we inferred that the PDT will facilitate the release of oxygen and the loaded drugs simultaneously.…”

Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy

“…In addition to the previously mentioned combination therapies, nanocarriers have shown great potential in enhancing cancer immunotherapy outcomes. For example, nanoparticles combined with MMP-2 inhibitors have been reported to improve outcomes in cancer photodynamic immunotherapy [ 150 ]. Similarly, MMP-sensitive nanomaterials, designed to degrade at a controlled rate within the TME, facilitate the release of their therapeutic contents and enhance T cell presence at the tumor site [ 151 ].…”

Application of Cyclodextrin for Cancer Immunotherapy

“…SB-3CT promoted both NKG2D/NKG2DL by antagonizing the MMP-2 pathway to block tumor cell immune escape. This study better integrates PDT and immunotherapy and provides unique insights into the future of PDT and immunotherapy [ 73 ].…”

“…Cyclodextrin analogues as immunotherapeutic drugs [32] Host-guest recognition with drugs for enhanced bioavailability [34,37,38,42,48,[60][61][62][63][65][66][67][68]73] Easy to modify on the primary and secondary faces for active targeting [34,42,65] Table 2. Cont.…”