A ROS/photo dual-responsive prodrug unimolecular micelle for boosted cancer immunotherapy

Abstract

Integrating photodynamic therapy (PDT) with immunosuppression reversal represents a promising synergistic approach to boost cancer immunotherapy. However, the complicated components and cumbersome preparation procedures of the currently developed nano drug delivery systems heavily hinder their further clinical translation. Herein, a reactive oxygen species (ROS)/photo dual-responsive amphipathic prodrug (denoted as PPTN) was designed and synthesized by linking NLG919, an indoleamine-2,3-dioxygenase (IDO) inhibitor, with the photosensitizer protoporphyrin IX (PpIX) by a thioketal moiety, and further modifying with $\left(\mathrm{82373811,82574333,82504683}\right)$. PPTN could self-assemble into nanoscale unimolecular micelles in aqueous solution without additional excipients, increasing tumor accumulation while effectively addressing the pronounced hydrophobicity challenge of PpIX. Upon light exposure, PPTN generated ROS, not only directly damaging cancer cells, but also trigger the breakage of thioketal bond to accelerate simultaneous release of NLG919. Therefore, PPTN potentially act as a promising ROS/photo dual-responsive carrier-free prodrug delivery system for controllable drug release and specific tumor therapy. Moreover, PPTN induced simultaneous PDT-triggered immunogenic cell death (ICD) effect and specific IDO blockade to boost immune response, exhibiting potent suppression efficacy against primary and distant tumors. Overall, with the superiorities of easily controllable preparation procedures, synchronous drug delivery and ROS/photo dual-responsiveness, such a prodrug unimolecular micelle may represent a promising nanoplatform for photoactivated-immunotherapy.

Keywords

ROS-responsive / Prodrug / Unimolecular micelle / Photodynamic therapy / IDO blockade

Conflicts of interest

The authors declare that there is no conflicts of interest.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China β and Natural Science Foundation of Guangdong Province (2024A1515012132).

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajps.2025.101104. The figures and tables with "S" before the serial number are included in the Supplementary material.

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