Tumor-Activated Carrier-Free Dual-Prodrug Nanoassemblies for Synergistic Chemo-Immunotherapy

Abstract Chemo-immunotherapy is limited by the poor bioavailability, nonspecific distribution, and systemic toxicity of free drugs. Here, we develop a reactive oxygen species (ROS)-responsive prodrug strategy by conjugating paclitaxel (PTX) and the TLR7/8 agonist resiquimod (R848) with a phenylboronic ester (PBE) moiety to generate two ROS-activatable prodrugs, PTX–PBE and R848–PBE. These prodrugs spontaneously coassemble into carrier-free nanoparticles (PR NPs) with ultrahigh loading efficiency and tunable drug ratios. PBE modification improves systemic stability while enabling ROS-triggered drug release in the tumor microenvironment, allowing PTX-mediated immunogenic cell death and R848-mediated innate immune activation. In colorectal cancer models, PR NPs suppress tumor growth, reduce systemic toxicity, and remodel the tumor immune microenvironment by promoting antitumor immune responses. This prodrug engineering strategy provides a high-loading, activatable, and carrier-free platform for chemo-immunotherapy with potential for cancer treatment.