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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,16]]},"abstract":"<jats:p>Immune checkpoint blockade has revolutionized oncology, yet low response rates and acquired resistance\u2014often driven by inadequate Programmed death-ligand 1 (PD-L1) suppression\u2014remain 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. 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