Herein, we examine the complexation and biological delivery of a short single-stranded antisense oligonucleotide (ASO) payload with four polymer derivatives that form two architectural variants (polyplexes and micelleplexes): a homopolymer poly(2-dimethylaminoethyl methacrylate) (D), a diblock polymer poly(ethylene glycol)methylether methacrylate--poly(2-dimethylaminoethyl methacrylate) (OD), and two micelle-forming variants, poly(2-dimethylaminoethyl methacrylate)--poly(-butyl methacrylate) (DB) and poly(ethylene glycol)methylether methacrylate--poly(2-dimethylaminoethyl methacrylate)--poly(-butyl methacrylate) (ODB). Both polyplexes and micelleplexes complexed ASOs, and the incorporation of an O brush enhances colloidal stability. Micellplexes are templated by the size and shape of the unloaded micelle and that micelle-ASO complexation is not sensitive to formulation/mixing order, allowing ease, versatility, and reproducibility in packaging short oligonucleotides. The DB micelleplexes promoted the largest gene silencing, internalization, and tolerable toxicity while the ODB micelleplexes displayed enhanced colloidal stability and highly efficient payload trafficking despite having lower cellular uptake. Overall, this work demonstrates that cationic micelles are superior delivery vehicles for ASOs denoting the importance of vehicle architecture in biological performance.
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