Predictive Amphiphile Design Enables Control of Self‐Assembled Nanoparticle‐Cell Membrane Interactions
8 affiliations
- 1Department of Polymer and Color Engineering Amirkabir University of Technology Tehran Iran
- 2Institut Für Chemie und Biochemie Organische Chemie Freie Universität Berlin Berlin Germany
- 3Department of Chemical Engineering Soft Matter Rheology and Technology KU Leuven Leuven Belgium
- 4Institut Für Chemie und Biochemie Forschungszentrum Für Elektronenmikroskopie Freie Universität Berlin Berlin Germany
- 5School of Biosciences Chanakya University Bengaluru India
- 6Department of Physics Freie Universitätät Berlin Berlin Germany
- 7Department of Chemistry and Materials Innovation Factory University of Liverpool Liverpool UK
- 8Department of Chemical Engineering University of Bath Bath UK
Abstract
Despite decades of development, the clinical translation of amphiphilic self‐assembled nanoparticles remains limited by the lack of a predictive molecular design framework, owing to the complex, dynamic behavior of nanoparticles and cell membranes. Here, we introduce a building‐block design strategy focused on amphiphile monomers rather than assembled nanoparticles, a critical distinction because nanoparticle morphology is not a fixed design parameter. This molecular framework links amphiphile chemical structure to programmable cellular interactions. Through predictive variation of headgroup and tail chemistries, we demonstrate that amphiphile design dictates nanoparticle fate at cell membranes. Fully fluorinated nanoparticles remain intact and adsorb onto the membrane surface, hydrocarbon nanoparticles rapidly dissociate and fuse, whereas semi‐fluorinated nanoparticles exhibit tunable kinetic delays, enabling programmable responses such as stability at rigid interfaces but dissociation at fluid membranes. Crucially, we identify the free energy of transfer (ΔG transfer)–the energetic difference between extracting an amphiphile from the nanoparticle and from the cell membrane–as a unified thermodynamic descriptor that accurately predicts behavior across simulations and experiments without requiring full‐system modeling. Collectively, this predictive, chemistry‐driven framework shifts the design paradigm from nanoparticle morphology to amphiphile chemistry, enabling the rational engineering of self‐assembled nanocarriers for targeted drug delivery and responsive drug release applications.
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BibTeX
@article{nami2026predictive,
title = {{Predictive Amphiphile Design Enables Control of Self‐Assembled Nanoparticle‐Cell Membrane Interactions}},
author = {Mahsa Nami and Tiffany Guitton‐Spassky and Farhad Sharif and Natalie Hanheiser and Riensqia Saudale and Jannik Gabriel and Aarti and Alireza Mirzaalipour and MohammadJavad Hafezi and Boris Schade and Abhishek Kumar Singh and Rainer Haag and Roland R. Netz and Hesam Makki},
journal = {Small (Weinheim an Der Bergstrasse, Germany)},
year = {2026},
month = aug,
doi = {10.1002/smll.75376},
url = {https://doi.org/10.1002/smll.75376},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Predictive Amphiphile Design Enables Control of Self‐Assembled Nanoparticle‐Cell Membrane Interactions
AU - Mahsa Nami
AU - Tiffany Guitton‐Spassky
AU - Farhad Sharif
AU - Natalie Hanheiser
AU - Riensqia Saudale
AU - Jannik Gabriel
AU - Aarti
AU - Alireza Mirzaalipour
AU - MohammadJavad Hafezi
AU - Boris Schade
AU - Abhishek Kumar Singh
AU - Rainer Haag
AU - Roland R. Netz
AU - Hesam Makki
PY - 2026
DA - 2026/08/22
JO - Small (Weinheim an Der Bergstrasse, Germany)
DO - 10.1002/smll.75376
UR - https://doi.org/10.1002/smll.75376
AB - Despite decades of development, the clinical translation of amphiphilic self‐assembled nanoparticles remains limited by the lack of a predictive molecular design framework, owing to the complex, dynamic behavior of nanoparticles and cell membranes. Here, we introduce a building‐block design strategy focused on amphiphile monomers rather than assembled nanoparticles, a critical distinction because nanoparticle morphology is not a fixed design parameter. This molecular framework links amphiphile chemical structure to programmable cellular interactions. Through predictive variation of headgroup and tail chemistries, we demonstrate that amphiphile design dictates nanoparticle fate at cell membranes. Fully fluorinated nanoparticles remain intact and adsorb onto the membrane surface, hydrocarbon nanoparticles rapidly dissociate and fuse, whereas semi‐fluorinated nanoparticles exhibit tunable kinetic delays, enabling programmable responses such as stability at rigid interfaces but dissociation at fluid membranes. Crucially, we identify the free energy of transfer (ΔG transfer)–the energetic difference between extracting an amphiphile from the nanoparticle and from the cell membrane–as a unified thermodynamic descriptor that accurately predicts behavior across simulations and experiments without requiring full‐system modeling. Collectively, this predictive, chemistry‐driven framework shifts the design paradigm from nanoparticle morphology to amphiphile chemistry, enabling the rational engineering of self‐assembled nanocarriers for targeted drug delivery and responsive drug release applications.
SN - 1613-6810
SN - 1613-6829
ER -