Abstract
Ligand spatial presentation and density play important roles in signaling pathways mediated by cell receptors and are critical parameters when designing protein-conjugated therapeutic nanoparticles. Here, we harness lipid phase separation to spatially control the protein presentation on lipid vesicles. We use this system to improve the cytotoxicity of TNF-related apoptosis inducing ligand (TRAIL), a therapeutic anticancer protein. Vesicles with phase-separated TRAIL presentation induce more cell death in Jurkat cancer cells than vesicles with uniformly presented TRAIL, and cytotoxicity is dependent on TRAIL density. We assess this relationship in other cancer cell lines and demonstrate that phase-separated vesicles with TRAIL only enhance cytotoxicity through one TRAIL receptor, DR5, while another TRAIL receptor, DR4, is less sensitive to TRAIL density. This work demonstrates a rapid and accessible method to control protein conjugation and density on vesicles that can be adopted to other nanoparticle systems to improve receptor signaling by nanoparticles.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2627-2634 |
| Number of pages | 8 |
| Journal | Nano letters |
| Volume | 22 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 13 2022 |
Funding
This work was supported in part by the Searle Funds at The Chicago Community Trust and the National Science Foundation under Grant Nos. 1844219 and 1844336. T.Q.V. was supported by the National Institutes of Health Training Grant (T32GM008449) through Northwestern University’s Biotechnology Training Program. J.A.P. gratefully acknowledges support from the Ryan Fellowship and the International Institute for Nanotechnology at Northwestern University. J.A.P. was supported by an NSF Graduate Research Fellowship. This work made use of the Northwestern RHLCCC Flow Cytometry Facility (NCI CA060553) and Northwestern NUANCE center (NSF ECCS-2025633 and NSF DMR-1720139). This work made use of the BioCryo facility of Northwestern University’s NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-2025633), the IIN, and Northwestern’s MRSEC program (NSF DMR-1720139). We thank the Kamat lab members for careful reading of the manuscript and the Mrksich group for helpful discussions.
Keywords
- Janus particles
- TRAIL
- lipid domains
- liposomes
- phase separation
- vesicles
ASJC Scopus subject areas
- Condensed Matter Physics
- Mechanical Engineering
- Bioengineering
- General Chemistry
- General Materials Science
