Aptamer-Functionalized DNA Frameworks as Targeted Drug Buffers for Concentration Regulation of Maytansine.

Abstract

Traditional chemotherapy often suffers from nonspecific distribution and poor drug concentration control, leading to compromised therapeutic efficacy and adverse effects. Mertansine (DM1), a potent cytotoxic agent with poor selectivity, dose-limiting toxicity, and a narrow therapeutic window, demands targeted delivery and precise concentration regulation for safety and efficacy. Herein, we constructed two Janus DNA triangular prism-based molecular buffers (3A-JTP-3S2 and A-MTP-3S2) for targeted DM1 delivery and concentration regulation. Both of the buffers integrate nucleolin-targeting aptamer (Apt-AS1411) for cancer cell recognition and DM1-specific aptamer (Apt-Seq2-X) for regulating DM1 concentration within a desired therapeutic range. When we evaluated their endocytic behaviors, 3A-JTP-3S2 was prone to lysosomal degradation via clathrin-mediated endocytosis. In contrast, A-MTP-3S2, a higher-order multivalent assembly built from 3A-JTP-3S2 units, forms an endocytosis-resistant DNA network that anchors onto cell membranes due to its enlarged size. We thus prioritized the latter for subsequent studies. A-MTP-3S2 delivered DM1 with favorable tumor-targeting ability across a total DM1 concentration (CDM1) range of 50-1000 nM, significantly killing A549 cancer cells (viability: 55.7 ± 8.15% - 50.84 ± 2.27%) while showing less impact on BEAS-2B normal cells (viability: 91.21 ± 2.72% - 76.31 ± 5.97%). Notably, even as CDM1 varied from 50 to 1000 nM, A-MTP-3S2 still maintained free DM1 at a relatively constant level (1-55 nM), confirming its great buffering capacity. Our work offers a facile strategy for simultaneous targeted delivery and precise concentration regulation of low-specific and high-toxic drugs.