Supramolecularly Engineered Circular Bivalent Aptamer for Enhanced Functional Protein Delivery

Abstract

Circular bivalent aptamers (cb-apt) comprise an emerging class of chemically engineered aptamers with substantially improved stability and molecular recognition ability. Its therapeutic application, however, is challenged by the lack of functional modules to control the interactions of cb-apt with therapeutics. We present the design of a β-cyclodextrin-modified cb-apt (cb-apt-βCD) and its supramolecular interaction with molecular therapeutics via host-guest chemistry for targeted intracellular delivery. The supramolecular ensemble exhibits high serum stability and enhanced intracellular delivery efficiency compared to a monomeric aptamer. The cb-apt-βCD ensemble delivers green fluorescent protein into targeted cells with efficiency as high as 80%, or cytotoxic saporin to efficiently inhibit tumor cell growth. The strategy of conjugating βCD to cb-apt, and subsequently modulating the supramolecular chemistry of cb-apt-βCD, provides a general platform to expand and diversify the function of aptamers, enabling new biological and therapeutic applications.

Enzyme-free synthesis of cyclic single-stranded DNA constructs containing a single triazole, amide or phosphoramidate backbone linkage and their use as templates for rolling circle amplification and nanoflower formation

“…These chemical cyclisation methods offer several advantages over the more limited enzymatic approach: they are cheaper and easier to carry out, allowing for the large-scale synthesis and purification of the cyclic oligonucleotide products; they can also be performed under a wider variety of conditions, including denaturing ones, and are therefore particularly useful for cyclising linear oligonucleotides which contain problematic secondary structure. The chemical cyclisation methods described here therefore provide a versatile expanded toolkit for the preparation of cyclic oligonucleotides, which have an expansive range of potential applications across molecular biology 61 – 65 and nanotechnology. 66 – 69 Here we investigated the use of the chemically modified cyclic products as templates for the production of long single-stranded DNA concatemers via the highly demanding rolling circle amplification reaction, an important technique which is currently attracting widespread interest.…”

Cyclodextrin Based Nanoparticles for Drug Delivery and Theranostics

“…123 Some recent case studies of the CDs in the optimal drug delivery of drugs, proteins, peptides and aptamers are reported in the Table 3. [124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140] CDs can be moulded into various types of formulation for proving ease the drug delivery by diverse routes of administration.…”

Circular Nucleic Acids: Discovery, Functions and Applications

“…The obtained circular bivalent aptamers were applied for in vivo fluorescence imaging, which validates their efficient accumulation and retention in tumors. When the circular bivalent aptamers were labeled with β‐cyclodextrin, they can be efficiently loaded with functional protein via host‐guest chemistry for therapeutic applications (Figure B) . Recently, Jia et al.…”