Tadpole-like cationic single-chain nanoparticles display high cellular uptake.

The successful delivery of nanoparticles (NPs) to cancer cells is dependent on various factors, including particle size, shape, surface properties such as hydrophobicity/hydrophilicity, charges, and functional moieties. Tailoring these properties has been explored extensively to enhance the efficacy of NPs for drug delivery. Single-chain polymer nanoparticles (SCNPs), notable for their small size (sub-20 nm) and tunable properties, are emerging as a promising platform for drug delivery. However, the impact of surface charge on the biological performance of SCNPs in cancer cells remains underexplored. In this study, we prepared a library of SCNPs with varying charge types (neutral, anionic, cationic, and zwitterionic), charge densities, charge positions, and crosslinking densities to evaluate their effects on cellular uptake in MCF-7 breast cancer cells. Key findings include that cationic SCNPs are more likely to translocate into cells than neutral, anionic, or zwitterionic counterparts. Furthermore, cellular uptake was enhanced with increased charge density (from 10 to 15 mol%) before reaching a critical point (20 mol%) where excessive positive charge led to NP adhesion to the cell membrane, resulting in cell death. We also found that the position of the charge on the polymer chain also impacted the delivery of NPs to cancer cells, with tadpole-shaped SCNPs achieving the highest uptake. Furthermore, crosslinking density significantly influenced cellular uptake, with SCNPs at 50% crosslinking conversion showing the highest cytosolic localization, while other densities resulted in retention primarily at the cell membrane. This study offers valuable insights into how charge type, density, position, and crosslinking density affect the biological performance of SCNPs, guiding the rational design of more effective and safer drug delivery systems.