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Targeted alpha therapy (TAT) has emerged as a promising strategy for cancer treatment by selectively delivering high linear energy transfer (LET) alpha-emitters to tumor cells while minimizing off-target toxicity. However, the clinical translation of alpha-emitters, particularly radium-223 (²²³Ra), remains challenging due to inefficient targeted delivery and uncontrolled release of recoil daughter products, leading to systemic toxicity.

Herein, a dual-locked pretargeted strategy was developed integrating platinum^IV (Pt^IV)-loaded hydrogel nanoparticles (HNPs) (HAQ@HNPs) and ²²³Ra-loaded HNPs (²²³Ra@HNPs) into an inverse electron demand Diels-Alder (IEDDA)-activated drug delivery system. In vitro cytotoxicity, ROS, and apoptosis, together with in vivo biodistribution, imaging, and therapeutic studies, were performed to evaluate the therapeutic efficacy and immune activation.

This caged dual-locked approach enables precise pretargeted accumulation at the tumor site, followed by rapid dissociation and controlled release of ²²³Ra and Pt^IV upon IEDDA-triggered activation, thereby ensuring high tumor specificity while minimizing systemic exposure. The synergistic combination of TAT and chemotherapy effectively disrupts redox homeostasis, induces immunogenic cell death (ICD), and elicits a robust antitumor immune response. Furthermore, when combined with programmed death-ligand 1 (PD-L1) blockade, this strategy significantly enhances systemic antitumor immunity, leading to robust inhibition of tumor growth and metastasis.

These findings underscore the potential of dual-locked pretargeted strategies to advance TAT by improving therapeutic efficacy and addressing the critical challenge of radionuclide leakage, paving the way for next-generation precision-targeted radiopharmaceuticals.