Abstract
The systemic delivery of exogenous proteins to cells within the brain and central nervous system (CNS) is challenging due to the selective impermeability of the blood-brain barrier (BBB). Herein, we hypothesized that protein delivery to the brain could be improved via functionalization with DNA aptamers designed to bind transferrin (TfR) receptors present on the endothelial cells that line the BBB. Using β-galactosidase (β-Gal) as a model protein, we synthesized protein spherical nucleic acids (ProSNAs) comprised of β-Gal decorated with TfR aptamers (Transferrin-ProSNAs). The TfR aptamer motif significantly increases the accumulation of β-Gal in brain tissue in vivo following intravenous injection over both the native protein and ProSNAs containing nontargeting DNA sequences. Furthermore, the widespread distribution of β-Gal throughout the brain is only observed for Transferrin-ProSNAs. Together, this work shows that the SNA architecture can be used to selectively deliver protein cargo to the brain and CNS if the appropriate aptamer sequence is employed as the DNA shell. Moreover, this highlights the importance of DNA sequence design and provides a potential new avenue for designing highly targeted protein delivery systems by combining the power of DNA aptamers together with the SNA platform.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1803-1810 |
| Number of pages | 8 |
| Journal | Bioconjugate Chemistry |
| Volume | 33 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 19 2022 |
Funding
This material is based on research sponsored by the Air Force Research Laboratory under agreement FA8650-15-2-5518. The U.S. Government is authorized to reproduce and distribute reprints for Governmental purposes notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of Air Force Research Laboratory or the U.S. Government. Research reported in this publication was also supported by the Lefkofsky Family Foundation, Polsky Urologic Cancer Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University at Northwestern Memorial Hospital, and the National Cancer Institute of the National Institutes of Health under Awards U54CA199091, R01CA208783, and P50CA221747. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. C.E.C. was supported by a Postdoctoral Fellowship, PF-20-046-01-LIB, from the American Cancer Society, as well as the Eden and Steven Romick Postdoctoral Fellowship through the American Committee for the Weizmann Institute of Science. This work was supported by the Northwestern University Keck Biophysics Facility and a Cancer Center Support Grant (NCI CA060553). This work made use of the IMSERC MS facility at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), the State of Illinois, and the International Institute for Nanotechnology (IIN). Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Microscopy was performed at the Biological Imaging Facility at Northwestern University (RRID:SCR_017767), graciously supported by the Chemistry for Life Processes Institute, the NU Office for Research, the Department of Molecular Biosciences, and the Rice Foundation. Portions of Figure 1 and 2 were created with BioRender.com.
ASJC Scopus subject areas
- Biotechnology
- Bioengineering
- Biomedical Engineering
- Pharmacology
- Pharmaceutical Science
- Organic Chemistry