# Heparin-Binding Proteins in the Nanoparticle Corona Enhance Cellular Uptake through Glycocalyx Interactions

## TL;DR

This study shows that proteins in the nanoparticle corona that bind to heparin can enhance nanoparticle uptake by interacting with the cell's glycocalyx.

## Contribution

The study reveals that glycocalyx interactions with heparin-binding proteins in the corona can actively promote nanoparticle uptake.

## Key findings

- HBPs like antithrombin and apolipoprotein E enhance NP surface retention and internalization.
- HBP-poor NPs show weak glycocalyx interactions and reduced uptake.
- Dyslipidemic sera produce HBP-enriched coronas that promote more efficient NP uptake.

## Abstract

Nanoparticles (NPs) designed for intracellular delivery
must first
navigate the cell-surface glycocalyx before reaching the plasma membrane
for internalization. Here, we hypothesized that the glycocalyx can
both hinder NP uptake via a barrier effect and enhance uptake by providing
recognition sites for corona proteins. To dissect these opposing mechanisms,
we prepared NPs with plasma protein coronas either enriched or depleted
in heparin-binding proteins (HBPs), along with model coronas containing
selected HBPs or non-HBPs. Biophysical assays confirmed strong heparin
interactions for HBP-rich NPs, whereas HBP-poor NPs showed weak or
no binding. To assess the role of corona–glycocalyx interactions
in NP uptake, we used glycocalyx-depleted cells, a chemical inhibitor,
and heparin and antithrombin competition assays. We found that canonical
HBPs within the protein corona, including antithrombin, apolipoprotein
E, and platelet factor 4, significantly enhanced NP surface retention
and internalization through protein–glycocalyx interactions.
In contrast, HBP-poor NPs showed weak or no interactions with the
glycocalyx and, correspondingly, reduced uptake. Significantly, these
findings also extended to physiologically derived coronas from control
and dyslipidemic sera, with the latter producing HBP-enriched coronas
that bound more strongly to heparin and promoted more efficient glycocalyx-dependent
NP uptake. These findings highlight the underappreciated role of the
glycocalyx in actively engaging with coronal HBPs to drive efficient
NP uptake. This insight underscores the need to expand corona engineering
beyond membrane receptor interactions, incorporating strategies that
optimize glycocalyx interactions for more effective NP delivery.