Rational Design Principles for Cell Membrane Coating of Nanoparticles

Abstract

Cell membrane coating offers a biomimetic strategy for drug delivery by combining the biological functions of natural membranes with the tunable properties of synthetic nanoparticles (NPs). The coating process influences membrane coverage and the biological performance of the resulting particles, making the selection of an appropriate coating method important. Although extrusion and sonication are widely used, how nanoparticle properties determine their relative performance remains insufficiently understood, and method selection is largely empirical. Here, we examine the interplay of drug loading, effective stiffness, and surface hydrophobicity in lipid NPs (LNPs), polymeric NPs (PNPs), and silica nanocapsules (SNCs). Hard SNCs favored sonication and soft SNCs favored extrusion in cellular uptake and full‐coating measurements. At comparable measured apparent Young's moduli, more hydrophobic PLGA NPs favored extrusion in cellular uptake, whereas more hydrophilic PLGA–PEG NPs favored sonication. Increasing bortezomib loading shifted the organic formulations toward extrusion despite the increased effective stiffness observed in the PNP loading series. At high loading, extrusion improved the LNP full‐coating ratio and reduced PNP macrophage uptake, while the PNP full‐coating ratios were comparable between methods. These complementary comparisons support our interpretation that surface hydrophobicity can override the stiffness‐associated method preference in the organic systems studied. Together, the findings provide a framework for selecting a coating method based on formulation composition, effective stiffness, and interfacial properties, with coating integrity and biological performance as complementary evaluation criteria.