Programmed cyclodextrin-based core–shell nanoparticles for cooperative TGF-β blockade to reverse immunosuppression post photodynamic therapy

Photodynamic therapy (PDT), as a clinical method of tumor treatment, has an advantage of immune activation, making it become an ideal adjuvant strategy for tumor immunotherapy. However, research data showed that the anti-tumor immune response of PDT was not lasting though existing, and would induce immunosuppression at the late stage. Our back-to-back previous research has just confirmed that TGF-β1 upregulation accounts for tumor immunosuppression aggravating post PDT and TGF-β blockade is a potential strategy to reverse this effect. How to realize the efficient coordination between PDT and TGF-β blockade becomes a burning question. Nanomedicine fully utilizing PDT principles could be a promising solution. In this study, a cyclodextrin-based core–shell nanoparticles (LC@HCDFC NPs) were designed to co-deliver LY2109761 (LY, a TGF-β1 inhibitor) and chlorin e6 for enhanced PDT combined with TGF-β blockade immunotherapy. Through utilizing PDT induced upregulation of CD44 and ROS, the inclusion complex shells of hyaluronic acid (HA) modified β-CD and ferrocene could realize incremental HA-CD44 mediated tumor targeting and ROS responsive drug release, and the cores of benzyl-modified poly (γ-glutamic acid) (BzPGA) improved the encapsulation efficiency of LY. Ultimately, through programmed delivery of TGF-β1 inhibitors, LC@HCDFC NPs not only enhanced the antitumor effect in situ, but reversed tumor immunosuppression and metastasis under the reshaped tumor microenvironment. This study provided enlightenment for programmed PDT in coordinate with TGF-β blockade immunotherapy and shed light on the efficient encapsulation and controlled release of TGF-β1 inhibitors.