Programmable DNA hydrogels for dual-mode PD-L1 suppression via polyvalent LYTAC mimics and transcriptional silencing

Abstract

Immune checkpoint blockade has revolutionized oncology, yet low response rates and acquired resistance—often driven by inadequate Programmed death-ligand 1 (PD-L1) suppression—remain significant barriers. While degradation-based proteolysis-targeting chimeras offer a promising alternative to traditional antibodies, targeting the intracellular and transcriptional drivers of checkpoint expression remains a challenge. We report a programmable, tumor-responsive DNA hydrogel platform, synthesized via rolling circle amplification, designed for the comprehensive, dual-mode modulation of PD-L1. This modular nucleic acid framework codelivers polyvalent aptamer-based lysosome-targeting chimeras (LYTAC mimics) to induce extracellular PD-L1 degradation and siSMARCAL1 to silence the chromatin-remodeling-driven transcriptional activation of PD-L1. By integrating localized, sequential release within the tumor microenvironment, this system achieves a synergistic “degrade-and-silence” effect that effectively dismantles PD-1/PD-L1-mediated immunosuppression while concurrently triggering immunogenic cell death. In murine melanoma models, the hydrogel significantly suppressed primary tumor growth and prevented postoperative recurrence, eliciting a robust and durable systemic antitumor immune response. Our findings establish a versatile, DNA-based materials strategy for programmable protein degradation and multilevel checkpoint modulation, offering a generalizable approach for enhancing the efficacy of cancer immunotherapy.