Ligand conformational entropy as a regime-switching descriptor of the electrostatic–uptake relationship in nanocarrier–immune cell interactions
- 1Clevix Lab, Clevix LLC, Hanoi, Vietnam
Abstract
Surface charge is widely regarded as a primary determinant of nanoparticle–immune cell interactions, yet nanocarriers with similar physicochemical profiles often exhibit markedly different biological outcomes. Here, we show that ligand conformational diversity, quantified through an information-theoretic descriptor (Hligand), is strongly associated with a regime transition in the relationship between surface charge and cellular uptake. Analysis of 105 gold nanoparticles from a benchmark protein corona dataset identifies a critical threshold at Hligand*≈1.76 bits (F = 47.3, p < 10−14): below this value, zeta potential is positively associated with uptake (r = +0.70), whereas above it the relationship reverses (r=−0.58), consistent with steric shielding by flexible surface ligands. Entropy-derived descriptors improve predictive performance across multiple model classes (ΔR2 up to +0.118), with gains concentrated in high-entropy regimes where physicochemical descriptors alone are insufficient. An analytical competition model captures this transition in a compact form (R2 = 0.550), with 2H*≈3.4 effective microstates marking a numerical balance point between electrostatic and steric contributions. Cross-dataset validation on 652 multi-material nanoparticles supports transferability of the descriptor framework (ΔR2=+0.181). We emphasize that Hligand is a constructed information-theoretic descriptor rather than a thermodynamic entropy, and that all findings are derived from retrospective analysis of in vitro datasets and not from controlled experimental manipulation. The identified threshold therefore represents a reproducible statistical pattern and a testable hypothesis for how ligand flexibility modulates interaction regimes. This framework provides a computable basis for organizing nanocarrier design hypotheses and motivates prospective validation in more complex carrier systems.
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BibTeX
@article{truong2026ligand,
title = {{Ligand conformational entropy as a regime-switching descriptor of the electrostatic–uptake relationship in nanocarrier–immune cell interactions}},
author = {Quynh Hoa Truong and Xuan Khanh Truong},
journal = {PLOS One},
year = {2026},
month = sep,
doi = {10.1371/journal.pone.0358239},
url = {https://doi.org/10.1371/journal.pone.0358239},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Ligand conformational entropy as a regime-switching descriptor of the electrostatic–uptake relationship in nanocarrier–immune cell interactions
AU - Quynh Hoa Truong
AU - Xuan Khanh Truong
PY - 2026
DA - 2026/09/18
JO - PLOS One
DO - 10.1371/journal.pone.0358239
UR - https://doi.org/10.1371/journal.pone.0358239
AB - Surface charge is widely regarded as a primary determinant of nanoparticle–immune cell interactions, yet nanocarriers with similar physicochemical profiles often exhibit markedly different biological outcomes. Here, we show that ligand conformational diversity, quantified through an information-theoretic descriptor (Hligand), is strongly associated with a regime transition in the relationship between surface charge and cellular uptake. Analysis of 105 gold nanoparticles from a benchmark protein corona dataset identifies a critical threshold at Hligand*≈1.76 bits (F = 47.3, p < 10−14): below this value, zeta potential is positively associated with uptake (r = +0.70), whereas above it the relationship reverses (r=−0.58), consistent with steric shielding by flexible surface ligands. Entropy-derived descriptors improve predictive performance across multiple model classes (ΔR2 up to +0.118), with gains concentrated in high-entropy regimes where physicochemical descriptors alone are insufficient. An analytical competition model captures this transition in a compact form (R2 = 0.550), with 2H*≈3.4 effective microstates marking a numerical balance point between electrostatic and steric contributions. Cross-dataset validation on 652 multi-material nanoparticles supports transferability of the descriptor framework (ΔR2=+0.181). We emphasize that Hligand is a constructed information-theoretic descriptor rather than a thermodynamic entropy, and that all findings are derived from retrospective analysis of in vitro datasets and not from controlled experimental manipulation. The identified threshold therefore represents a reproducible statistical pattern and a testable hypothesis for how ligand flexibility modulates interaction regimes. This framework provides a computable basis for organizing nanocarrier design hypotheses and motivates prospective validation in more complex carrier systems.
SN - 1932-6203
ER -