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The effect of the serum corona on interactions between a single nano-object and a living cell

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ABSTRACT

Nanoparticles (NPs) which enter physiological fluids are rapidly coated by proteins, forming a so-called corona which may strongly modify their interaction with tissues and cells relative to the bare NPs. In this work the interactions between a living cell and a nano-object, and in particular the effect on this of the adsorption of serum proteins, are directly examined by measuring the forces arising as an Atomic Force Microscope tip (diameter 20 nm) - simulating a nano-object - approaches and contacts a cell. We find that the presence of a serum protein corona on the tip strongly modifies the interaction as indicated by pronounced increase in the indentation, hysteresis and work of adhesion compared to a bare tip. Classically one expects an AFM tip interacting with a cell surface to be repelled due to cell elastic distortion, offset by tip-cell adhesion, and indeed such a model fits the bare-tip/cell interaction, in agreement with earlier work. However, the force plots obtained with serum-modified tips are very different, indicating that the cell is much more compliant to the approaching tip. The insights obtained in this work may promote better design of NPs for drug delivery and other nano-medical applications.

No MeSH data available.


A schematic representation of the engulfment mechanism which results in the differences between indentation by a bare tip, left, and a corona–coated tip, right.For the bare tip the elastic forces (due to deformation of the cytoskeleton elements, shown as black lines) act together with weak forces arising from the membrane adhering to the tip, left. For the corona coated tip, right, its engulfment by the cell membrane results in a substantial attractive force arising from corona-membrane recognition – specific interactions are schematically indicated - which largely offsets the elastic repulsion due to deformation of the cytoskeleton.
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f7: A schematic representation of the engulfment mechanism which results in the differences between indentation by a bare tip, left, and a corona–coated tip, right.For the bare tip the elastic forces (due to deformation of the cytoskeleton elements, shown as black lines) act together with weak forces arising from the membrane adhering to the tip, left. For the corona coated tip, right, its engulfment by the cell membrane results in a substantial attractive force arising from corona-membrane recognition – specific interactions are schematically indicated - which largely offsets the elastic repulsion due to deformation of the cytoskeleton.

Mentions: How can all these observations on Group II (where the tip is exposed to serum and its corona is attributed to proteins adsorbed from the serum133536, as discussed earlier), namely the incompatibility with the model of Eq. (1), and the very large indentation, hysteresis and adhesion (relative to Group I where the tip is bare), be explained? As the protein-decorated tip contacts and indents the cell, the cell undergoes a strikingly-large deformation with little resistance. That is, the tip continuously presses on the cell without reaching the trigger force, which is only reached after a deep indentation. We stress the difference in the length-scales of the indentations involved - of order of a micron for group II rather than of order of 200 nm for group I. We attribute this as follows: Since, as earlier noted, the effective cell elasticity as a whole (essentially its modulus E*) is due to the cytoskeleton and is unaffected by the corona, one would expect a large elastic resistance Felastic to such a deformation (to depth x) of the cell. If we assume that the modulus E* is unchanged with extent of indentation50 we may approximate this by taking just the first term in Eq. (1) which dominates at such large indentations since it varies as x2 while the offsetting adhesion term varies as x. For a deformation x = 1 μm, this yields an expected resistance force Felastic =  ≈ 6.5 × 10−10 N. From Fig. 3(B) however, the actual force F required for a penetration of 1 μm is only ca. 0.4 × 10−10 N. The difference between the force Felastic required for a 1 μm deformation of the cell and the actual force needed for such a penetration by the corona-coated tip is thus ca. 6 × 10−10 N. In other words, an attraction between the tip and the cell of that magnitude (ca. 6 × 10−10 N) must have occurred to offset the repulsion that would have been expected from the elastic deformation for such an indentation. We attribute this attraction to the engulfment by the cell membrane of the (corona-coated) AFM tip, and/or the beginning of formation of a pit which is associated with a large local change and rearrangement of the cytoskeleton as happens in several endocytosis mechanisms. e.g. Caveole or Clatherin mediated endocytosis5152. This is illustrated schematically in Fig. 7. Clearly complete endocytosis (as would be the case for a small NP31) cannot occur, since the AFM tip – whose footprint on the cell surface increases progressively as it indents the cell – cannot be ‘swallowed up’ by the cell.


The effect of the serum corona on interactions between a single nano-object and a living cell
A schematic representation of the engulfment mechanism which results in the differences between indentation by a bare tip, left, and a corona–coated tip, right.For the bare tip the elastic forces (due to deformation of the cytoskeleton elements, shown as black lines) act together with weak forces arising from the membrane adhering to the tip, left. For the corona coated tip, right, its engulfment by the cell membrane results in a substantial attractive force arising from corona-membrane recognition – specific interactions are schematically indicated - which largely offsets the elastic repulsion due to deformation of the cytoskeleton.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382918&req=5

f7: A schematic representation of the engulfment mechanism which results in the differences between indentation by a bare tip, left, and a corona–coated tip, right.For the bare tip the elastic forces (due to deformation of the cytoskeleton elements, shown as black lines) act together with weak forces arising from the membrane adhering to the tip, left. For the corona coated tip, right, its engulfment by the cell membrane results in a substantial attractive force arising from corona-membrane recognition – specific interactions are schematically indicated - which largely offsets the elastic repulsion due to deformation of the cytoskeleton.
Mentions: How can all these observations on Group II (where the tip is exposed to serum and its corona is attributed to proteins adsorbed from the serum133536, as discussed earlier), namely the incompatibility with the model of Eq. (1), and the very large indentation, hysteresis and adhesion (relative to Group I where the tip is bare), be explained? As the protein-decorated tip contacts and indents the cell, the cell undergoes a strikingly-large deformation with little resistance. That is, the tip continuously presses on the cell without reaching the trigger force, which is only reached after a deep indentation. We stress the difference in the length-scales of the indentations involved - of order of a micron for group II rather than of order of 200 nm for group I. We attribute this as follows: Since, as earlier noted, the effective cell elasticity as a whole (essentially its modulus E*) is due to the cytoskeleton and is unaffected by the corona, one would expect a large elastic resistance Felastic to such a deformation (to depth x) of the cell. If we assume that the modulus E* is unchanged with extent of indentation50 we may approximate this by taking just the first term in Eq. (1) which dominates at such large indentations since it varies as x2 while the offsetting adhesion term varies as x. For a deformation x = 1 μm, this yields an expected resistance force Felastic =  ≈ 6.5 × 10−10 N. From Fig. 3(B) however, the actual force F required for a penetration of 1 μm is only ca. 0.4 × 10−10 N. The difference between the force Felastic required for a 1 μm deformation of the cell and the actual force needed for such a penetration by the corona-coated tip is thus ca. 6 × 10−10 N. In other words, an attraction between the tip and the cell of that magnitude (ca. 6 × 10−10 N) must have occurred to offset the repulsion that would have been expected from the elastic deformation for such an indentation. We attribute this attraction to the engulfment by the cell membrane of the (corona-coated) AFM tip, and/or the beginning of formation of a pit which is associated with a large local change and rearrangement of the cytoskeleton as happens in several endocytosis mechanisms. e.g. Caveole or Clatherin mediated endocytosis5152. This is illustrated schematically in Fig. 7. Clearly complete endocytosis (as would be the case for a small NP31) cannot occur, since the AFM tip – whose footprint on the cell surface increases progressively as it indents the cell – cannot be ‘swallowed up’ by the cell.

View Article: PubMed Central - PubMed

ABSTRACT

Nanoparticles (NPs) which enter physiological fluids are rapidly coated by proteins, forming a so-called corona which may strongly modify their interaction with tissues and cells relative to the bare NPs. In this work the interactions between a living cell and a nano-object, and in particular the effect on this of the adsorption of serum proteins, are directly examined by measuring the forces arising as an Atomic Force Microscope tip (diameter 20 nm) - simulating a nano-object - approaches and contacts a cell. We find that the presence of a serum protein corona on the tip strongly modifies the interaction as indicated by pronounced increase in the indentation, hysteresis and work of adhesion compared to a bare tip. Classically one expects an AFM tip interacting with a cell surface to be repelled due to cell elastic distortion, offset by tip-cell adhesion, and indeed such a model fits the bare-tip/cell interaction, in agreement with earlier work. However, the force plots obtained with serum-modified tips are very different, indicating that the cell is much more compliant to the approaching tip. The insights obtained in this work may promote better design of NPs for drug delivery and other nano-medical applications.

No MeSH data available.