Modulating Phagocytic Cell Sequestration by Tailoring Nanoconstruct Softness

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Abstract
The effect of nanoparticle size, shape and surface properties on cellular uptake has been extensively investigated for its basic science and translational implications. Recently, softness is emerging as a design parameter for modulating the interaction of nanoparticles with cells and the biological microenvironment. Here, circular, quadrangular and elliptical polymeric nanoconstructs of different sizes are realized with a Young’s modulus ranging from ∽ 100 kPa (soft) to 10 MPa (rigid). The interaction of these nanoconstructs with professional phagocytic cells is assessed via confocal microscopy and flow cytometry analyses. Regardless of the size and shape, softer nanoconstructs evade up to 5 times more efficiently cellular uptake, by bone marrow derived monocytes, as compared to rigid nanoconstructs. Soft circular and quadrangular nanoconstructs are equally uptaken by professional phagocytic cells (< 15%), soft elliptical particles are more avidly internalized (< 60%) possibly because of the larger size and elongated shape, whilst over 70% of rigid nanoconstructs of any shape and size are uptaken. Inhibition of actin polymerization via cytochalasin D reduces internalization propensity for all nanoconstruct types. High-resolution live cell microscopy documents that soft nanoconstructs mostly establish short-lived (< 30 sec) interactions with macrophages thus diminishing the likelihood of recognition and internalization. The bending stiffness is identified as a discriminating factor for internalization, whereby particles with a bending stiffness slightly higher than cells would more efficiently oppose internalization as compared to stiffer or softer particles. These results confirm that softness is a key parameter in modulating the behavior of nanoparticles and are expected to inspire the design of more efficient nanoconstructs for drug delivery, biomedical imaging and immunomodulatory therapies.
Funding Information
  • Associazione Italiana per la Ricerca sul Cancro (17664)
  • FP7 Ideas: European Research Council (616695)

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