Nanoparticles consisting of metal-organic frameworks (NMOFs) modified with nucleic acid binding strands are synthesized. The NMOFs are loaded with a fluorescent agent or with the anticancer drug doxorubicin, and the loaded NMOFs are capped by hybridization with a complementary nucleic acid that includes the ATP-aptamer or the ATP-AS1411 hybrid aptamer in caged configurations. The NMOFs are unlocked in the presence of ATP via the formation of ATP-aptamer complexes, resulting in the release of the loads. As ATP is overexpressed in cancer cells, and since the AS1411 aptamer recognizes the nucleolin receptor sites on the cancer cell membrane, the doxorubicin-loaded NMOFs provide functional carriers for targeting and treatment of cancer cells. Preliminary cell experiments reveal impressive selective permeation of the NMOFs into MDA-MB-231 breast cancer cells as compared to MCF-10A normal epithelial breast cells. High cytotoxic efficacy and targeted drug release are observed with the ATP-AS1411-functionalized doxorubicin-loaded NMOFs. The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adfm.201702102.conductivity material for fuel cells, [16][17][18] and as a composite material for sensing applications. [4,[19][20][21] Substantial recent efforts are directed toward the development of stimulitriggered reconfigurable nucleic acid structures (DNA switches and DNA machines). [22][23][24][25][26][27] Porous inorganic materials, e.g., SiO 2 nanoparticles, [28] microcapsules, [29] or organic hydrogels, [30][31][32] were loaded with substrates (or drugs) and caged with stimuli-responsive nucleic acid locks. In the presence of appropriate triggers, the stimuli-responsive loaded matrices were unlocked, resulting in the release of the loads. Different stimuli such as pH, [33] light, [34] heat, [35] catalytic nucleic acids, [36] or aptamer-ligand complexes [37] were used to unlock the substrate-loaded materials. Naturally, the capping of the highly porous substrate-loaded MOFs with stimuli-responsive DNAs could yield efficient DNA/ MOFs hybrids as drug delivery systems. Despite the chemical modification of MOFs with stimuli-responsive chemical capping units, [38][39][40][41][42][43] the integration of nucleic acids with MOFs is scarce and involved only the carrying of DNA. [44][45][46][47] Recently, we reported [48] on the successful entrapment of substrates in macrocrystalline MOFs protected by pH-responsive or K + -stabilized G-quadruplex capping units and the triggered unlocking of the MOFs, and the release of loads, by altering the pH, or their treatment with 18-crown-6 ether. While this study demonstrated the successful synthesis of stimuli-responsive DNAgated, substrate-loaded, microcrystalline MOFs, these materials suffer from a basic limitation because they are nonpermeable into cells. That is, their potential application as stimuli-responsive drug carriers is limited. The synthesis of nanometersized MOF particles is well established, [49][50][51][52][53][54] but ...