Dual-locked targeted alpha-emitter enhanced tumor immunotherapy via Diels-Alder reaction-based self-immolative molecular cage strategy.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.