Photosensitive pro-drug nanoassemblies harboring a chemotherapeutic dormancy function potentiates cancer immunotherapy

Immunotherapy combined with effective therapeutics such as chemotherapy and photody-namic therapy have been shown to be a successful strategy to activate anti-tumor immune responses for improved anticancer treatment. However, developing multifunctional biodegradable, biocompatible, low-toxic but highly efficient, and clinically available transformed nano-immunostimulants remains a challenge and is in great demand. Herein, we report and design of a novel carrier-free photo -chemother-apeutic nano-prodrug COS-BA/Ce 6 NPs by combining three multifunctional componentsda self -assembled natural small molecule betulinic acid (BA), a water-soluble chitosan oligosaccharide (COS), and a low toxic photosensitizer chlorin e6 (Ce6)dto augment the antitumor efficacy of the im-mune adjuvant anti-PD-L1-mediated cancer immunotherapy. We show that the designed nanodrugs harbored a smart and distinctive dormancy characteristic in chemotherapeutic effect with desired lower cytotoxicity, and multiple favorable therapeutic features including improved 1O2 generation induced by the reduced energy gap of Ce6, pH-responsiveness, good biodegradability, and biocompatibility, ensuring a highly efficient, synergistic photochemotherapy. Moreover, when combined with anti-PD-L1 therapy, both nano-coassembly based chemotherapy and chemotherapy/photodynamic therapy (PDT) could effec-tively activate antitumor immunity when treating primary or distant tumors, opening up potentially attrac-tive possibilities for clinical immunotherapy. 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Immunotherapy combined with chemotherapy and photodynamic therapy has been successfully used to enhance anti-tumor immune responses. However, the development of multifunctional and biodegradable nano-immunostimulants remains a challenge. In this study, a carrier-free nano-prodrug COS-BA/Ce6 NPs was designed, which showed improved antitumor efficacy by combining three multifunctional components. The nano-drugs exhibited low cytotoxicity, pH-responsiveness, good biodegradability, and biocompatibility, making them highly efficient for synergistic photochemotherapy. When combined with anti-PD-L1 therapy, they effectively activated antitumor immunity, showing potential for clinical immunotherapy.