Self‐Assembled and Size‐Controllable Oligonucleotides Nanospheres for Effective Antisense Gene Delivery via Endocytosis‐Independent Pathway

The development of efficient gene delivery vectors has experienced two major challenges, endo/lysosomal escape and intracellular release. To address these problems, we developed an oligonucleotides (ONs) template‐assisted polymerization approach to create ONs nanospheres as gene vectors. In this approach, guanidinium‐containing strained disulfide monomers were organized on the ONs templates, greatly increasing their local effective concentrations. Consequently, ring‐opening disulfide‐exchange polymerization between monomers was accelerated, further facilitating the self‐assembly of ONs nanospheres. These nanospheres were size controllable by varying the length of ONs templates. Importantly, nanospheres could be directly delivered into cytosol via an endocytosis‐independent pathway and followed by intracellular depolymerisation in the reductive cytosolic environment to release the packaged ONs, resulting in efficient gene silence. By taking advantages of facile assembly, direct intracellular delivery and good biocompatibility, ONs nanospheres hold great promise as candidates for gene therapy.

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