ROS-Responsive mPEG–PCL Nanoparticles for Co-Delivery of Paclitaxel Prodrug and R848 in Synergistic Chemo-Immunotherapy

Abstract

Chemo-immunotherapy aims to integrate chemotherapy-induced antigen release with innate immune activation to achieve enhanced antitumor efficacy. However, the pharmacokinetic mismatch and systemic toxicity of free small molecules often compromise the synergistic effects. Herein, we propose a reactive oxygen species (ROS)-responsive nanoplatform based on mPEG–PCL for the co-delivery of a paclitaxel (PTX) prodrug and the TLR7/8 agonist R848. The nanoparticles remain stable under physiological conditions while releasing drug in oxidative tumor microenvironments, thereby achieving synchronous intratumoral delivery and activation. In vitro, the system exhibited efficient intracellular uptake and potent cytotoxicity against tumor cells while maintaining low toxicity toward normal cells due to prodrug design. Moreover, the platform effectively induced immunogenic cell death and promoted dendritic cell maturation, highlighting its capacity for chemo-immunotherapeutic synergy. This co-delivery strategy provides a versatile approach to realize controllable and safe chemo-immunotherapy through stimuli-responsive nanomedicine design.