Intelligent Modular DNA Lysosome-Targeting Chimera Nanodevice for Precision Tumor Therapy.

Abstract

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