Gene

Genetic enhancement

Cell biology

Molecular biology

Biology

Materials science

Catabolism

Gene delivery

Upstream (networking)

Biochemistry

Deoxyribozyme

Computer science

Aptamer

Gene silencing

Computational biology

Computer network

Drug delivery

Nanotechnology

Enzyme

Ribozyme

Chemistry

Biophysics

Cleave

Angewandte Chemie International Edition

DNAzyme‐based gene therapy holds immense prospects for effectively treating severe diseases, yet is constrained with inefficient delivery and unconditional activation. Herein, we designed a bioinspired self‐catabolic DNA nanocapsule for sustaining tumor‐specific cascade activation of therapeutic DNAzyme. The exquisite DNAzyme was temporarily masked by the self‐excising DNAzyme in the hierarchical rolling circle replication (RCR) nanostructures, thus stayed in an inactive state in physiological fluids. Through the multivalent tumor‐anchoring aptamer strands, the RCR nanocapsule was specifically accumulated in cancer cells and was sequentially activated for motivating the ultimate DNAzyme‐mediated gene silencing via the intelligent stimuli‐responsive cascade DNAzyme activation. By virtue of the programmable RCR assembly strategy, our compact DNAzyme nanoplatform shows great promise for developing versatile smart gene therapeutics and personalized nanomedicines.

A Self‐Catabolic Multifunctional DNAzyme Nanosponge for Programmable Drug Delivery and Efficient Gene Silencing