Folding an RCA Scaffold into an Intelligent Coiled\nNanosnake for Precise/Synergistic RNAi-/Chemotherapy of Cancer

An\nRCA product is a promising scaffold for the construction of\nDNA nanostructures, but so far, there is no RCA scaffold-based dynamic\nreconfigurable nanorobot for biological applications. In this contribution,\nwe develop an intracellular stimuli-responsive reconfigurable coiled\nDNA nanosnake (N-Snake) by using incomplete aptamer-functionalized\n(A) DNA tetrahedrons (T) to fold a long tandemly repetitive DNA strand\nsynthesized by rolling circle amplification reaction (R) with the\nhelp of palindromic fragment (P). A DNA-assembled product, ARTP, including\nspiked aptamers, can retain the structural integrity even if exposed\nto fetal bovine serum (FBS) for 24 h and displays substantially enhanced\ntarget molecule-dependent cellular internalization efficiency. ARTP\ncontains tetrahedral containers and linear containers, so that there\nare 500 doxorubicins (DOXs) and 12.5 siRNAs per ARTP. Moreover, ARTP\ncan precisely transport anticancer drugs to cancerous sites and controllably\nrelease via the structural reconfiguration upon intracellular stimuli,\nalmost 100% inhibiting tumor growth without detectable systemic toxicity\nowing to the synergistic RNAi-/Chemotherapy. Apparently, coiled N-snake,\nDOX/siPlk1-loaded ARTP, can specifically enter tumor cells, uncoil\nupon intracellular stimuli, and attack the cells from the inside,\nexerting precise cancer therapy.