Self-deliverable and self-immolative prodrug nanoassemblies as tumor targeted nanomedicine with triple cooperative anticancer actions

Stimulus-responsive self-assembling prodrug-based nanomedicine has emerged as a novel paradigm in controlled drug delivery. All-trans retinoic acid (RA), one of vitamin A metabolites, induces apoptotic cancer cell death, but its clinical applications are limited by weak anticancer efficacy. To fully maximize the therapeutic potential of RA, we exploited the unique chemistry of arylboronic acid which undergoes hydrogen peroxide (H₂O₂)-triggered degradation to release quinone methide (QM) that alkylates glutathione (GSH) to disrupt redox homeostasis and is also converted into hydroxybenzyl alcohol (HBA) to suppress the expression of vascular endothelial growth factor (VEGF). Here, we report that boronated retinoic acid prodrug (RABA) can be formulated into self-deliverable nanoassemblies which release both RA and QM in a H₂O₂-triggered self-immolative manner to exert cooperative anticancer activities. RABA nanoassemblies exert anticancer effects by inducing reactive oxygen species (ROS)-mediated apoptosis, eliciting immunogenic cell death (ICD) and suppressing angiogenic VEGF expression. The excellent anticancer efficacy of RABA nanoassemblies can be explained by benefits of self-assembling prodrug-based drug self-delivery and cooperative anticancer actions. The design strategy of RABA would provide a new insight into the rational design of self-deliverable and self-immolative boronated prodrug nanoassemblies for targeted cancer therapy.