Several biological barriers (e.g., the plasma membrane, the formed endosomes after cellular uptake, and eventually, the nuclear envelope) are generally responsible for limiting the amount of delivered therapeutic cargoes at the intracellular level. Previously, a new family of nanobioconjugates was developed as an alternative to overcome such issues by favoring cell penetration and endosomal escape. The nanobioconjugates were obtained by immobilizing the cell-penetrating peptide Buforin II (BUF-II) and the <i>E. Coli’s</i> transmembrane protein OmpA on modified magnetite nanoparticles (MNPs). Here, we propose to extend this approach to silica NPs (SNPs) and fullerenol as alternative nanostructured supports to conjugate the same potent cell-penetrating agents. This was conceptualized under the rationale that the same cell-penetrating molecule conjugated to different nanocarriers may exhibit different internalization and trafficking routes and differential localization within various subcellular compartments, which is attractive for targeted delivery. SNPs and fullerenols have gained attention as nanocarriers due to their unique structural characteristics and physicochemical properties, which can be tailored to improve their interaction with human cells. The size, charge, composition, morphology, and correct immobilization of the translocating agents were assessed via FT-IR and UV-visible spectroscopies, DLS, Electrophoretic Mobility, SEM, TEM, TGA, and XPS. Also, the extent of cell internalization (in Vero and THP-1 cells) was evaluated via confocal microscopy by calculating cell coverage, while endosomal escape was quantified by measuring colocalization of rhodamine B-labeled nanobioconjugates with Lysotracker Green. The obtained results confirmed superior cell membrane translocation capabilities, without significantly compromising cell viability. Moreover, standardized hemocompatibility tests demonstrated negligible hemolytic effect, as well as a low propensity to induce platelet aggregation. Taken together our findings strongly suggest that the developed platforms hold much promise for developing more potent drug delivery vehicles to address major challenges in the field of pharmacology.

Nanobioconjugates based on translocating peptides immobilized on silica nanoparticles and fullerenol: potential platforms for highly-potent delivery vehicles

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ACS Fall 2022

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