Ultrasound-Responsive Azide Nano-prodrugs Enable Spatiotemporal Activation of TLR7/8 Agonists for Tumor Therapy

Systemic immunotoxicity caused by off-target activation is still a critical obstacle to clinical translation of imidazoquinoline (IMDQ) drugs, a kind of TLR7/8 agonists. Here, we present an ultrasound-responsive, azide-modified IMDQ nano-prodrug (IMDQ-N3 NPs) that enables spatiotemporally controlled activation through ultrasound, improving the selectivity and safety. Concomitantly, riboflavin-based sonosensitizers were co-delivery to these nanoparticles, increasing their local concentration surrounding the prodrug, achieving a 12.2-fold enhancement in the ultrasonic reduction rate of IMDQ-N3. In murine models, IMDQ-N3 NPs demonstrated no weight loss and negligible systemic inflammatory factor elevation relative to equivalent-dose unmodified IMDQ. Combined with ultrasound irradiation, IMDQ-N3 NPs demonstrated 35.2-fold higher tumor distribution of active drug compared to non-irradiated free IMDQ-N3, achieving 95.7% tumor suppression and 60% long-term survival. Flow cytometry analysis revealed enhanced dendritic cell maturation, cytotoxic T-cell infiltration, and durable immune memory. This work establishes a generalizable platform for precision delivery of immunostimulatory agents, addressing key translational challenges in cancer immunotherapy.