Plasmid-templated control of DNA-cyclodextrin nanoparticle morphology through molecular vector design for effective gene delivery

Engineering self-assembled superstructures through complexation of plasmid DNA (pDNA) and single-isomer nanometric size macromolecules (molecular nanoparticles) is a promising strategy for gene delivery. Notably, the functionality and overall architecture of the vector can be precisely molded at the atomic level by chemical tailoring, thereby enabling unprecedented opportunities for structure/self-assembling/pDNA delivery relationship studies. Beyond this notion, by judiciously preorganizing the functional elements in cyclodextrin (CD)-based molecular nanoparticles through covalent dimerization, here we demonstrate that the morphology of the resulting nanocomplexes (CDplexes) can be tuned, from spherical to ellipsoidal, rod-type, or worm-like nanoparticles, which makes it possible to gain understanding of their shape-dependent transfection properties. The experimental findings are in agreement with a shift from chelate to cross-linking interactions on going from primary-face- to secondary-face-linked CD dimers, the pDNA partner acting as an active payload and as a template. Most interestingly, the transfection efficiency in different cells was shown to be differently impacted by modifications of the CDplex morphology, which has led to the identification of an optimal prototype for tissue-selective DNA delivery to the spleen in vivo.This study was supported by the Spanish Ministerio de Economía y Competitividad (contract numbers CTQ2012‐30821, CTQ2015‐65972‐R, SAF2016‐76083‐R, CTQ2015‐64425‐C2‐1‐R, and CTQ2015‐64425‐C2‐2‐R), the Junta de Andalucía (contract number FQM2012‐1467), the University Complutense of Madrid (project no. UCMA05‐33‐010), and the European Regional Development Funds (FEDER and FSE)