In Vitro and In-Silico\nAssessment of Gaussian Curvature-driven\nInternalization Kinetics of Nanoparticles

Nanoparticles have been of significant interest in various\nbiomedical\ndomains such as drug delivery, gene delivery, cytotoxicity analysis,\nand imaging. Despite the synthesis of a variety of nanoparticles,\ntheir cellular uptake efficiency remains a substantial obstacle, with\nonly a small fraction of delivered nanoparticles (NPs) have been reported\nto traverse the cell membrane within 24 h. Consequently, higher doses\nare often necessitated, leading to increased toxicity concerns. In\nthis investigation, we illustrate that nanoparticles having negative\nGaussian curvature demonstrate rapid and efficient internalization\ninto cells by lowering the energy barrier for membrane bending. Specifically,\nthree types of gold nanoparticles; gold nanorods (GNR), gold nanodogbones\nat pH 4 (GDB4), and gold nanodogbones at pH 6 (GDB6) were synthesized,\nwith Gaussian curvatures of 0, −166.91, and −376.62,\nrespectively. Cellular uptake studies conducted via ICP-OES analysis\nreveal that GDB6 is taken up 140% more in A549 cells and 77% more\nin NIH3T3 cells compared to GNR. Confocal microscopy-based uptake\nstudies further confirm the higher uptake of GDB6 compared to GNR.\nAdditionally, molecular simulations indicate that GDB nanoparticles\nexhibit a significantly larger free energy change during translocation\ncompared to GNR, emphasizing the impact of nanoparticle shape on uptake\nand translocation through the membrane and validating the efficacy\nof negative Gaussian curvature in enhancing cellular uptake, consistent\nwith experimental observations. Overall, our findings emphasize the\nimportance of nanoparticle curvature modulation in maximizing cellular\nuptake efficiency for improved biomedical applications, providing\nvaluable insights into the design of nanomaterials for drug delivery\npurposes.