Stiffness of HIV‐1 Mimicking Polymer Nanoparticles Modulates Ganglioside‐Mediated Cellular Uptake and Trafficking

Abstract

The monosialodihexosylganglioside, GM3, and its binding to CD169 (Siglec‐1) have been indicated as key factors in the glycoprotein‐independent sequestration of the human immunodeficiency virus‐1 (HIV‐1) in virus‐containing compartments (VCCs) in myeloid cells. Here, lipid‐wrapped polymer nanoparticles (NPs) are applied as a virus‐mimicking model to characterize the effect of core stiffness on NP uptake and intracellular fate triggered by GM3‐CD169 binding in macrophages. GM3‐functionalized lipid‐wrapped NPs are assembled with poly(lactic‐co‐glycolic) acid (PLGA) as well as with low and high molecular weight polylactic acid (PLAlMW and PLAhMW) cores. The NPs have an average diameter of 146 ± 17 nm and comparable surface properties defined by the self‐assembled lipid layer. Due to differences in the glass transition temperature, the Young's modulus (E) differs substantially under physiological conditions between PLGA (EPLGA = 60 ± 32 MPa), PLAlMW (EPLAlMW = 86 ± 25 MPa), and PLAhMW (EPLAhMW = 1.41 ± 0.67 GPa) NPs. Only the stiff GM3‐presenting PLAhMW NPs but not the softer PLGA or PLAlMW NPs avoid a lysosomal pathway and localize in tetraspanin (CD9)‐positive compartments that resemble VCCs. These observations suggest that GM3‐CD169‐induced sequestration of NPs in nonlysosomal compartments is not entirely determined by ligand–receptor interactions but also depends on core stiffness.

Effect of Physico-Chemical Properties of Nanoparticles on Their Intracellular Uptake

“…There are several nanoparticle parameters that influence their uptake into the cells [44][45][46][47][48][49][50][51], and some recent studies exemplifying these are shown in Table 1. A brief overview of NP physicochemical properties and their impact on internalization is described below.…”

“…Quantifying the effect of NP elasticity on cellular uptake is challenging because of experimental difficulties in measuring the micro-and nano-scale mechanical properties of NPs [51,108]. One of the problems in the study of the elasticity effects on the NP endocytosis is the fact that many physiochemical properties of NPs are strongly related to each other.…”

Elucidating Carbohydrate-Protein Interactions Using Nanoparticle-Based Approaches

“…Solid nanoparticles consist of polymeric, metallic, or semiconducting materials, which exhibit lower surface mobility compared with biological lipid membranes. Contrary to metallic and semiconducting nanoparticles, polymeric nanoparticles confer tunable mechanical modulus, which allows the emulation of various viral core stiffness which is correlated with viral maturation state and infectivity (Kol et al, 2007 ; Eshaghi et al, 2020 ). In addition, several pH-responsive self-assembled polymeric nanoparticles can be disassembled in low pH environments such as tumor region or endolysosome in the cell, providing targeted release of the cargo (Liao et al, 2018 ; Pan et al, 2018 ).…”

Tuning the Elasticity of Polymersomes for Brain Tumor Targeting

“…[ 7 ] Optimization of physical parameters was also investigated to improve drug delivery of nanoformulations. These studies showed that nanoformulation physical properties such as size, [ 8 ] shape, [ 9 ] surface chemistry, [ 10 ] and elasticity [ 11 ] play critical roles in regulating nano‐bio interactions including cell uptake, blood circulation, tumor penetration, and accumulation. Understanding how physical properties affect underlying biomechanisms should shed light on the design of drug delivery vectors with higher efficiency.…”

“…The elasticity is the ability of an object resist deformation caused by stress and to return to its original state when the stress is removed. [ 12 ] The factors that may potentially impact the elasticity of nanoformulations include the intrinsic property of materials, [ 13 ] crosslinking density, [ 14 ] thickness, [ 15 ] polymer volume fraction [ 11e ] and the encapsulated components [ 11 , 16 ] (Table S1 , Supporting Information). To date, how exactly elasticity of nanoformulations affect their biological performance is still unclear or even debatable.…”