Abstract
Maximizing the tissue-targeting efficiency of nanomaterials while also protecting them from rapid clearance from the bloodstream and limiting their immunogenicity remains a central problem in the field of systemic-administered nanomedicine. Herein, we introduce a generalizable strategy to simultaneously increase tumor accumulation, prolong blood circulation, and limit nonspecific immune activation of nanomaterials via peptide-based, tumor-responsive, "sheddable"coatings. Spherical nucleic acids (SNAs) were designed and synthesized to contain an exterior coating composed of zwitterionic polypeptides with recognition sequences for tumor-associated proteases. In the presence of matrix metalloproteinases (MMPs), the polypetide coating is rapidly cleaved, leading to increased cellular uptake of these SNAs, relative to SNAs containing nonsheddable shells. Moreover, the zwitterionic nature of the polypeptide shell shields the SNAs from immune system recognition, which extends their blood circulation time and improves tumor accumulation and in vivo cellular uptake relative to control SNAs with no protective coating. Taken together, these results indicate that this strategy is a viable method for increasing nanoparticle tumor accumulation and can have utility for the systemic delivery of oligonucleotides and nanomaterials to target cells in vivo with low immunogenicity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 10931-10942 |
| Number of pages | 12 |
| Journal | ACS nano |
| Volume | 16 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 26 2022 |
Funding
Research reported in this publication was supported by the Lefkofsky Family Foundation, the 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 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). Imaging work was performed at the Northwestern University Center for Advanced Molecular Imaging generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. 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.
Keywords
- PEGylation
- immunogenicity
- matrix metalloproteinase-cleavable
- spherical nucleic acids
- tumor accumulation
- zwitterionic peptides
ASJC Scopus subject areas
- General Engineering
- General Materials Science
- General Physics and Astronomy