Ultrasound-activated erythrocyte membrane-camouflaged Pt (II) layered double hydroxide enhances PD-1 inhibitor efficacy in triple-negative breast cancer through cGAS-STING pathway-mediated immunogenic cell death.

Abstract

Rationale: Immunogenic cell death (ICD) offers a promising avenue for the treatment of triple-negative breast cancer (TNBC). However, optimizing immune responses remains a formidable challenge. This study presents the design of RBCm@Pt-CoNi layered double hydroxide (RmPLH), an innovative sonosensitizer for sonodynamic therapy (SDT), aimed at enhancing the efficacy of programmed cell death protein 1 (PD-1) inhibitors by inducing robust ICD responses. Methods: Pt-CoNi layered double hydroxide (LDH) nanocages were synthesized using a two-step method, followed by functionalization with red blood cell membranes to prepare RmPLH. The in vitro assessments included evaluations of cell toxicity, cellular uptake, and sonodynamic effects of RmPLH. Key mechanisms-such as oxidative stress, DNA damage, pyroptosis, cGAS/STING pathway activation, and inhibition of cellular migration and invasion-were explored under varying treatment conditions in 4T1 cells. Tumor-bearing mice were employed to evaluate tumor-targeting capabilities and the synergistic tumor-suppressive effects of RmPLH combined with PD-1 inhibitors. Comprehensive safety evaluations, including blood tests, biochemical analyses, and histopathological examinations, were also conducted. Results: The synthesized Pt-CoNi LDH exhibited a uniform rhombic dodecahedral nanocage morphology with an average particle size of approximately 231 nm. Encapsulation with red blood cell membranes conferred prolonged systemic circulation, enhanced tumor targeting, and reduced immune clearance for RmPLH. Upon ultrasound (US) stimulation, the LDH released substantial levels of reactive oxygen species (ROS) and platinum ions. The ROS effectively induced endoplasmic reticulum stress and ferroptosis, while platinum ions facilitated DNA crosslinking, triggering significant DNA damage. ROS-induced pyroptosis released inflammatory mediators and damage-associated molecular patterns (DAMPs), which activated the cGAS/STING pathway and reinforced ICD. Combining RmPLH with PD-1 inhibitors significantly enhanced therapeutic efficacy against TNBC. Furthermore, safety assessments confirmed the excellent biocompatibility and biosafety of RmPLH. Conclusion: The integration of RmPLH with PD-1 inhibitors substantially amplifies ICD, fostering robust antigen-specific T cell immunity and offering a promising therapeutic strategy for TNBC. This study represents a pioneering application of Pt (II)-based LDH nanocages in oncology, laying a foundation for future innovations in tumor immunotherapy.