Bioactive clusters promoting cell penetration and nucleic acid complexation for drug and gene delivery applications: from designed to self-assembled and responsive systems

Abstract

Bioactive low-molecular-weight compounds are actively pursued, as an alternative to macromolecules, for biomedical applications such as drug and gene delivery. However, achieving effective biomolecular surface recognition with small molecules is a considerable challenge. We review herein recent progresses that have been made in the identification of bioactive cationic clusters that promote cell penetration and nucleic acid complexation and vectorisation. We further emphasize the emerging use of self-assembly processes, based on supramolecular interactions and/or dynamic covalent chemistry, for generating bioactive cationic clusters. Interestingly, the introduction of molecular and/or supramolecular dynamics endows reversibility to the multivalent recognition processes, thereby paving the way toward the development of "smart" adaptive and responsive devices that emulate the behaviour of natural systems for the dynamic control of bioactivity.

Plasmid‐Templated Control of DNA–Cyclodextrin Nanoparticle Morphology through Molecular Vector Design for Effective Gene Delivery

“…[9][10][11][12][13] Further developmentso fa ccurates ynthetic manipulation [14] and (bio)orthogonal click-chemistry methodologies [15][16][17] have enabled the access to single-isomer,n anometric-sized molecules having ap ersistent topology and ap re-oriented pattern of functional groups, generally termed molecular nanoparticles, with surgical precision. [18][19][20] Ab attery of single-isomer3 Dd isplays tailored towards nucleic acid complexation, targeting, and delivery has thus been produced, [21,22] examples record on covering cyclodextrin (CD), [23][24][25][26][27][28][29][30] calixarene, [31][32][33][34][35][36] macrocyclic peptides, [37][38][39][40] fullerene, [41][42][43][44] pillarene, [45][46][47] or cyclotrehalanp latforms. [48,49] These studies have focused on the influence of the molecular architecture of the vectoro nt he self-assembling and the nucleic acid delivery capabilities; however, none of them has pursued shape control of the vector-nucleic acid nanoparticles for the systematic study of its role fort he transfection efficiency.…”

Glycosylated Cell‐Penetrating Peptides (GCPPs)

“…The results reported herein highlight the potential of the glycosylationo fp enetratingp eptides to modulatetheir activity. [17][18][19][20][21][22][23][24][25] Interesting penetrating properties were further discovered in different naturala nd artificial structures, such as polyprolines, [26] guanidinyl glycosides, [27,28] b-peptides, [29] peptiden ucleic acids (PNAs), [30] nonpeptidic guanidinylated dendritic structures, [31] self-assembled nanofibers, [32,33] synthetic polymers, [34][35][36][37] supramolecular structures, [38][39][40] and polydisulfides. [14] These studies also showed that oligolysines were less effective than that of the oligoarginines analogues, [15] and triggered the development of synthetic penetrating oligoarginines.…”

Selective Localization of Hierarchically Assembled Particles to Plasma Membranes of Living Cells

“…A number of methods exist for the fabrication of particles with complex architectures which may be used to mimic naturally occurring intricate structures . For instance, electrohydrodynamic (EHD) cojetting allows for rapid fabrication of particles with complex architectures . Compared to conventional electrospraying, EHD cojetting involves extrusion of two or more polymer solutions through a nozzle under a laminar flow regime (Figure S1, Supporting Information).…”