ROS-Responsive Nanoparticles as Self-Assembling Photoimmunostimulants for Photodynamic Immunotherapy of Breast Cancer

To address the challenges in the treatment of triple-negative breast cancer, we have developed a self-assembling nanoparticle system for the codelivery of a thioketal (TK)-linked Reximide (R848) dimer (TKdR) and the photosensitizer Chlorin e6 (Ce6). These nanoparticles, termed photosensitizer-stabilized self-assembled TKdR nanoparticles (psTKdR NPs), self-assemble through hydrophobic interactions without the need for surfactants. They exhibited good physiological stability, rapid intracellular uptake, and a simple preparation. Once internalized into tumor cells, photodynamic therapy (PDT) effectively induced immunogenic cell death, while Ce6 generated reactive oxygen species under specific light activation, leading to the cleavage of the TK bond and the release of R848. This, in turn, drove cellular immune responses and promoted dendritic cell maturation and M1 macrophage polarization. This synergistic approach enhanced the combined antitumor efficacy of the drugs. In vivo studies demonstrated that PDT-initiated psTKdR Nps immunotherapy significantly suppressed the growth of primary tumors, showing substantial advantages over stand-alone PDT treatment. In vivo, the Ce6-only group achieved a tumor growth inhibition rate of approximately 57%, whereas the psTKdR NPs group significantly enhanced this effect to 85%, demonstrating the superior antitumor efficacy of combined PDT and immunotherapy. Immune activation was mediated through Toll-like receptor signaling and cytokine interactions, leading to T cell and lymphocyte proliferation and activation. This study underscores the potential of ROS-responsive carrier-free Nps as a powerful tool for photodynamic immunotherapy, presenting a potential approach for treating breast cancer and other malignancies.