Language
English
Publication Date
6-17-2026
Journal
ACS Nanoscience Au
DOI
10.1021/acsnanoscienceau.5c00170
PMID
42327930
PMCID
PMC13281171
PubMedCentral® Posted Date
2-20-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Antibody conjugation is essential for targeted lipid nanoparticle (LNP) delivery, but here we show that click-chemistry produces artifacts that confound accurate measurement of covalent antibody-LNP bonding. We demonstrate that hydrophobic interactions between the most common click alkyne linker, dibenzocyclooctyne (DBCO), and the inherently hydrophobic LNP surface drive extensive nonspecific antibody physisorption, even in the absence of LNP azide groups. This physisorption yields artificially high apparent conjugation efficiencies measured by chromatographic methods. In contrast, less hydrophobic liposomes exhibit azide-dependent conjugation, highlighting a consequence of nanoparticle surface chemistry. Plasma incubation rapidly displaces physisorbed antibodies from LNPs, confirming their weak, noncovalent association, whereas covalently bound antibodies remain attached and enable effective in vivo targeting. Substituting DBCO with the less hydrophobic bicyclononyne (BCN) also reduces nonspecific associations. Our findings reveal hydrophobicity as a hidden variable in antibody–LNP conjugation and establish new standards for quantitative and reproducible measurement of targeted LNPs.
Keywords
Lipid Nanoparticles, Click Chemistry, Antibody Conjugation, Targeting, Nanomedicine, Drug Delivery
Published Open-Access
yes
Recommended Citation
Brysgel, Taylor V; Hood, Elizabeth D; Milosavljevic, Aleksa; et al., "Decoupling Physisorption from Chemisorption in Clickable Lipid Nanoparticles" (2026). Faculty, Staff and Students Publications. 8616.
https://digitalcommons.library.tmc.edu/baylor_docs/8616