Currently, the treatment of
triple-negative breast cancer (TNBC) is limited by the special pathological characteristics of this disease. In recent years,
photodynamic therapy (
PDT) has created new hope for the treatment of TNBC. Moreover,
PDT can induce immunogenic cell death (ICD) and improve
tumor immunogenicity. However, even though
PDT can improve the immunogenicity of TNBC, the inhibitory immune microenvironment of TNBC still weakens the antitumor immune response. Therefore, we used the neutral
sphingomyelinase inhibitor
GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by TNBC cells to improve the
tumor immune microenvironment and enhance antitumor immunity. In addition, bone mesenchymal stem cell (BMSC)-derived sEVs have good
biological safety and a strong
drug loading capacity, which can effectively improve the efficiency of
drug delivery. In this study, we first obtained primary BMSCs and sEVs, and then the
photosensitizers Ce6 and
GW4869 were loaded into the sEVs by electroporation to produce immunomodulatory photosensitive nanovesicles (Ce6-
GW4869/sEVs). When administered to TNBC cells or orthotopic TNBC models, these photosensitive sEVs could specifically target TNBC and improve the
tumor immune microenvironment. Moreover,
PDT combined with GW4869-based
therapy showed a potent synergistic antitumor effect mediated by direct killing of TNBC and activation of antitumor immunity. Here, we designed photosensitive sEVs that could target TNBC and regulate the
tumor immune microenvironment, providing a potential approach for improving the effectiveness of TNBC treatment. STATEMENT OF SIGNIFICANCE: We designed an immunomodulatory photosensitive nanovesicle (Ce6-
GW4869/sEVs) with the
photosensitizer Ce6 to achieve
photodynamic therapy and the neutral
sphingomyelinase inhibitor
GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by
triple-negative breast cancer (TNBC) cells to improve the
tumor immune microenvironment and enhance antitumor immunity. In this study, the immunomodulatory photosensitive nanovesicle could target TNBC cells and regulate the
tumor immune microenvironment, thus providing a potential approach for improving the treatment effect in TNBC. We found that the reduction in
tumor sEVs secretion induced by
GW4869 improved the
tumor-suppressive immune microenvironment. Moreover, similar therapeutic strategies can also be applied in other kinds of
tumors, especially immunosuppressive
tumors, which is of great value for the clinical translation of
tumor immunotherapy.