Cationic‐Hydrophilic Di‐Block Copolymers: Surface‐Shielded Vectors for Gene Delivery

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ABSTRACTTo tackle the main challenges in gene therapy, synthetic polycationic vectors are developed for nucleic acid (NA) delivery. In this work, vectors based on di‐block copolymers consisting of a methacrylate‐type cationic block and an electroneutral hydrophilic block are designed and synthesized to condense NA into compact particles shielded with a bioinert hydrophilic polymer layer. The results confirm that the cationic vector blocks, containing permanently charged trimethylammonium (TMA) or tributylphosphonium (TBP) groups and 0–20 mol% hydrophobic butyl groups, are able to efficiently complex DNA to form 100 to 200 nm spheroids, while the hydrophilic blocks based on 2‐methacryloyloxyethylphosphorylcholine or N‐(2‐hydroxypropyl) methacrylamide coat the nanoparticle surfaces with an electroneutral polymer layer. Additionally, pH‐responsive hydrazone bonds are incorporated between the TMA and TBP groups and the main polymer backbone of the polycationic block to ensure hydrolysis of the hydrazone bond. Theoretically, this should be accompanied by DNA release from the complex in a mildly acidic environment inside the cells while maintaining its stability under neutral blood conditions. In summary, this model study provides insight into the process of complexation/decomplexation of NA by pH‐responsive di‐block polycationic vectors. The results may contribute to the development of safe and efficient delivery systems for gene therapy applications.