A size/charge/targeting changeable nano-booster to realize synergistic photodynamic-immunotherapy with high safety

Abstract

Photodynamic therapy (PDT) is widely performed to augment immune checkpoint blockade (ICB) therapy. Unfortunately, adverse events of ICB antibodies and inefficient delivery of photosensitizers restrict the efficacy of synergistic photodynamic-immunotherapy. Herein, the size/charge/targeting changeable nano-booster (NC@Ce6) is developed for synergistic photodynamic-immunotherapy, which is generated by co-loading the anti-programmed death-ligand 1 (aPDL1) and photosensitizer (Ce6) into the acid-responsive nanocomplex (NC). NC@Ce6 can be selectively transformed into smaller nanoparticles (∼28 nm) with a higher positive charge in the weakly acidic tumor microenvironment (TME), thereby improving the tumor penetration of aPDL1 and Ce6. Notably, structural alterations are accompanied by exposures of tumor cell-targeting ligand (phenylboronic acid) that can facilitate the specific interaction of aPDL1 with tumor cells while minimizing its adverse events (fatalityrate: aPDL1 50% vs. NC@Ce6 0%). Similarly, this process allows efficient delivery of Ce6 to the tumor cell and leads more precise control of ROS generation, thereby activating strong tumor immunogenic cell death. More importantly, NC@Ce6-mediated photodynamic immunotherapy increases the intra-tumoral infiltration of CD8+ T cells reshaping the immunosuppressive TME. The resultsin vitroandin vivoconsistently indicate this nanosystem exhibits a high potent antitumor efficacy in two different tumor models, presenting a promising strategy that could boost antitumor immunity without fatality events.