“In the field of targeted alpha therapy for cancer treatment, a dual-locked pretargeted strategy was developed, integrating platinumIV (PtIV)-loaded hydrogel nanoparticles (HNPs) and radium-223 (223Ra)-loaded HNPs into an inverse electron demand Diels–Alder (IEDDA)-activated drug delivery system. This caged dual-locked approach enables precise pretargeted accumulation at the tumor site, followed by rapid dissociation and controlled release of 223Ra and PtIV 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.”