Spherical Polyelectrolyte Brushes for Nonviral Efficient Gene Delivery

The development of safe and effective nonviral vectors remains a critical bottleneck in gene therapy and mRNA delivery. Traditional cationic polymers such as poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) exhibit strong nucleic acid binding but suffer from poor colloidal stability and inconsistent transfection outcomes due to ill-defined architectures. Here, we present a structurally defined nanocarrier based on spherical polyelectrolyte brushes (SPBs), featuring dense PDMAEMA chains radially grafted onto polymer cores via surface-initiated metal-free photoemulsion polymerization. This strategy enables uniform brush growth in aqueous media, yielding particles with high charge density, tunable dimensions, and excellent dispersibility. The resulting SPBs effectively condense plasmid DNA, exhibit low cytotoxicity across multiple mammalian cell lines, and deliver plasmid DNA with a dose-dependent and cell-specific efficiency. Upon delivery of phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-expressing plasmids, SPBs achieved robust transfection efficiency and functional gene expression, as evidenced by upregulated PTEN and reduced phosphorylated protein kinase B (p-AKT) levels. Compared to polyethylenimine (PEI) and Lipofectamine 3000 (Lipo3000), SPBs showed comparable or superior gene expression, particularly in difficult-to-transfect cell lines. This work demonstrates the potential of SPBs as an ideal low-toxicity gene delivery system.