In Vitro and In-Silico Assessment of Gaussian Curvature-driven Internalization Kinetics of Nanoparticles

Nanoparticles have been of significant interest in various biomedical domains such as drug delivery, gene delivery, cytotoxicity analysis, and imaging. Despite the synthesis of a variety of nanoparticles, their cellular uptake efficiency remains a substantial obstacle, with only a small fraction of delivered nanoparticles (NPs) have been reported to traverse the cell membrane within 24 h. Consequently, higher doses are often necessitated, leading to increased toxicity concerns. In this investigation, we illustrate that nanoparticles having negative Gaussian curvature demonstrate rapid and efficient internalization into cells by lowering the energy barrier for membrane bending. Specifically, three types of gold nanoparticles; gold nanorods (GNR), gold nanodogbones at pH 4 (GDB4), and gold nanodogbones at pH 6 (GDB6) were synthesized, with Gaussian curvatures of 0, -166.91, and -376.62, respectively. Cellular uptake studies conducted via ICP-OES analysis reveal that GDB6 is taken up 140% more in A549 cells and 77% more in NIH3T3 cells compared to GNR. Confocal microscopy-based uptake studies further confirm the higher uptake of GDB6 compared to GNR. Additionally, molecular simulations indicate that GDB nanoparticles exhibit a significantly larger free energy change during translocation compared to GNR, emphasizing the impact of nanoparticle shape on uptake and translocation through the membrane and validating the efficacy of negative Gaussian curvature in enhancing cellular uptake, consistent with experimental observations. Overall, our findings emphasize the importance of nanoparticle curvature modulation in maximizing cellular uptake efficiency for improved biomedical applications, providing valuable insights into the design of nanomaterials for drug delivery purposes.