Intelligent\nModular DNA Lysosome-Targeting Chimera\nNanodevice for Precision Tumor Therapy

Lysosome\ntargeting chimeras (LYTACs) have emerged as a powerful\nmodality that can eliminate traditionally undruggable extracellular\ntumor-related pathogenic proteins, but their low bioavailability and\nnonspecific distribution significantly restrict their efficacy in\nprecision tumor therapy. Developing a LYTAC system that can selectively\ntarget tumor tissues and enable a modular design is crucial but challenging.\nWe here report a programmable nanoplatform for tumor-specific degradation\nof multipathogenic proteins using an intelligent modular DNA LYTAC\n(IMTAC) nanodevice. We employ circular DNA origami to integrate predesigned\nmodular multitarget protein binding sites and pH-responsive protein\ndegradation promoters that specifically recognize cell-surface lysosome-shuttling\nreceptors in tumor tissues. By precisely manipulating the stoichiometry\nand modularity of promoters and ligands targeting diverse proteins,\nthe IMTAC nanodevice enables accurate localization and delivery into\ntumor tissues, where the acidic tumor microenvironment triggers degradation\nswitch activation, multivalent binding, and efficient degradation\nof various prespecified proteins. The tissue-specificity and multiple\nligands in IMTACs significantly improve the drug utilization rate\nwhile reducing off-target effects. Importantly, this system demonstrates\nthe capability of collabo-rative degradation of EGFR and PDL1 in tumor\ntissue for combined targeting and immunity therapy of hepatocellular\ncarcinoma (HCC), resulting in obvious tumor necrosis and inhibition\nof tumor growth in vivo even at low concentrations. This study presents\na unique strategy for building a general, intelligent, modular, and\nsimple encoded nanoplatform for designing precision medicine degraders\nand developing proprietary antitumor drugs.