Hydroxyethyl starch conjugates co-assembled nanoparticles promote photodynamic therapy and antitumor immunity by inhibiting antioxidant systems

Photodynamic therapy (PDT) can produce high levels of reactive oxygen species (ROS) to kill tumor cells and induce antitumor immunity. However, intracellular antioxidant systems, including glutathione (GSH) system and thioredoxin (Trx) system, limit the accumulation of ROS, resulting in compromised PDT and insufficient immune stimulation. Herein, we designed a nanomedicine PtHPs co-loading photosensitizer pyropheophorbide a (PPa) and cisplatin prodrug Pt-COOH(IV) (Pt (IV)) based on hydroxyethyl starch (HES) to inhibit both GSH and Trx antioxidant systems and achieve potent PDT as well as antitumor immune responses. Specifically, HES-PPa and HES-Pt were obtained by coupling HES with PPa and Pt (IV), and assembled into nanoparticle PtHPs by emulsification method to achieve the purpose of co-delivery of PPa and Pt (IV). PtHPs improved PPa photostability while retaining PPa photodynamic properties. <i>In vitro</i> experiments showed that PtHPs reduced GSH, inhibited Trx system and had better cell-killing effect and ROS generation ability. Subcutaneous tumor models showed that PtHPs had good safety and tumor inhibition effect. Bilateral tumor models suggested that PtHPs promoted the release of damage-associated molecular patterns and the maturation of dendritic cells, induced T cell-mediated immune responses, and thus suppressed the growth of both primary and distal tumors. This study reports a novel platinum-based nanomedicine and provides a new strategy for boosting PDT therapy-mediated antitumor immunity by overcoming intrinsic antioxidant systems.