APE1/ATP dual-input AND-gated DNA nanoflowers as a colloidal nanoplatform for logic-controlled cancer cell imaging and DNAzyme gene silencing.

Abstract

Colloidal DNA nanoflowers have emerged as promising biointerface platforms for cancer theranostics owing to their porous architectures, robust nuclease resistance, and favorable cytocompatibility. Integrating molecular logic gates into such bio-colloidal systems enables stringent spatial and temporal control over therapeutic activation, thereby minimizing off-target effects. Herein, we fabricate a APE1/ATP dual-input AND-gated DNA nanoflower (AMDNF) via rolling circle amplification (RCA). The resulting AMDNF features a flower-like organic-inorganic hybrid scaffold co-assembling abundant tandem functional modules, including nucleolin-targeting AS1411 aptamers, ATP-recognition units, cleavable DNAzymes, and in situ co-precipitated Mg2⁺ cofactors. This nanosystem operates under strict AND logic: fluorescence recovery and DNAzyme reconstitution occur exclusively upon the coexistence of elevated ATP and overexpressed APE1, establishing a dual-biomarker molecular filter that prevents inadvertent activation in normal cells. Following receptor-mediated endocytosis and lysosomal escape, the AMDNF generates fluorescent signals for in situ cancer cell imaging, while the restored DNAzyme catalytically cleaves survivin mRNA, effectively silencing anti-apoptotic gene expression and suppressing tumor cell proliferation. Notably, this logic-gated colloidal platform exhibits negligible cytotoxicity toward normal mammary epithelial cells, underscoring its biosafety advantage. This work provides a facile strategy for constructing logic-responsive DNA-based colloidal nanoplatforms and offers new insights into precision cancer biointerfaces.