Radiotherapy-ignited dual-stage prodrug nanoplatform for cascade activation of toll-like receptor 7/8 agonist and reignition of antitumor immunity.

Abstract

A major bottleneck in radio-immunotherapy is the inability to precisely couple the localized stimulus of radiotherapy (RT) with the systemic action of immunotherapeutics. To bridge this gap, we developed a chemically engineered RT-ignited nanoplatform that productively harnesses the biochemical consequences of RT to precisely activate immunotherapy locally, thereby amplifying its benefits while minimizing systemic exposure. The platform co-delivers a hydrogen sulfide (H₂S)-responsive prodrug of toll-like Toll-like receptor 7/8 (TLR7/8) agonist imiquimod (IMQ) using a reactive oxygen species (ROS)-sensitive, targeted nanocarrier. RT ignites a biochemical sequence: ROS bursts disassemble the carrier, and the subsequent H₂S upregulation cleaves the prodrug, ensuring tumor-localized drug release. This RT-primed, sequentially activated therapy profoundly enhances antitumor immunity by inducing immunogenic cell death (ICD), activating antigen-presenting cells (APCs), and overcoming systemic immunosuppression, culminating in durable tumor regression and immunological memory. This study highlights a chemistry-driven approach to spatially and temporally confine immune activation to the tumor site, effectively broadening the therapeutic window and transforming RT-induced biochemical changes into a precise trigger for systemic immunity.