A Dual-Mechanism Targeted Cross-Convergence Prodrug Activation Strategy Enabled by Biological Stimulus Amplification...

Current prodrug strategies in clinical practice still face several challenges, such as insufficient targeting specificity, substantial systemic toxicity, and complex administration protocols, which urgently need to be resolved. Here, we present a dual-mechanism targeted cross-convergence activation strategy, which couples tumor-targeting prodrug delivery with biological stimulus amplification to achieve precise and highly efficient drug release. The system comprises 2 components: (a) BTW2 nanoparticles, a reactive oxygen species (ROS)-responsive prodrug conjugated to biotin for tumor-selective accumulation via the enhanced permeability and retention effect and biotin-receptor-mediated uptake, and (b) IR-808, a heptamethine dye that targets tumors through organic-anion-transporting polypeptides and amplifies intracellular ROS. Upon cross-convergence at tumor sites, IR-808 elevates ROS levels, triggering thioketal linker cleavage in BTW2 nanoparticles to release W436, a potent tubulin inhibitor. The released W436 further amplifies ROS, establishing a self-reinforcing positive feedback loop. This strategy enables precision therapy for primary and metastatic cancers via spatiotemporally controlled, self-reinforcing drug release.