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Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer—From Bench to Bedside
SIMPLE SUMMARY: Nanotechnology enables new ways to diagnose and treat cancer. Nanomedicines can increase payload concentration at the disease site, reduce toxicity, and enhance therapeutic effects compared to drugs in their “free” form. Spherical Nucleic Acids (SNAs) emerged as a new class of oligon...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996871/ https://www.ncbi.nlm.nih.gov/pubmed/35406387 http://dx.doi.org/10.3390/cancers14071615 |
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author | Mahajan, Akanksha S. Stegh, Alexander H. |
author_facet | Mahajan, Akanksha S. Stegh, Alexander H. |
author_sort | Mahajan, Akanksha S. |
collection | PubMed |
description | SIMPLE SUMMARY: Nanotechnology enables new ways to diagnose and treat cancer. Nanomedicines can increase payload concentration at the disease site, reduce toxicity, and enhance therapeutic effects compared to drugs in their “free” form. Spherical Nucleic Acids (SNAs) emerged as a new class of oligonucleotide nanotherapeutics that are currently being explored as gene-regulatory and immunostimulatory architectures to overcome drug resistance and immunosuppression in solid tumors. This review highlights seminal studies that identified SNAs as a powerful platform for gene regulation, the activation of innate immunity, and the development of next-generation cancer vaccines, discusses recent efforts to translate fundamental discovery from the laboratory into the clinic, and provides an outlook on future research aimed at harnessing the full therapeutic potential of the SNA platform. ABSTRACT: Spherical Nucleic Acids (SNAs) emerged as a new class of nanotherapeutics consisting of a nanoparticle core densely functionalized with a shell of radially oriented synthetic oligonucleotides. The unique three-dimensional architecture of SNAs protects the oligonucleotides from nuclease-mediated degradation, increases oligonucleotide bioavailability, and in the absence of auxiliary transfection agents, enables robust uptake into tumor and immune cells through polyvalent association with cell surface pattern recognition receptors. When composed of gene-regulatory small interfering (si)RNA or immunostimulatory DNA or RNA oligonucleotides, SNAs silence gene expression and induce immune responses superior to those raised by the oligonucleotides in their “free” form. Early phase clinical trials of gene-regulatory siRNA-based SNAs in glioblastoma (NCT03020017) and immunostimulatory Toll-like receptor 9 (TLR9)-agonistic SNAs carrying unmethylated CpG-rich oligonucleotides in solid tumors (NCT03086278) have shown that SNAs represent a safe, brain-penetrant therapy for inhibiting oncogene expression and stimulating immune responses against tumors. This review focuses on the application of SNAs as precision cancer therapeutics, summarizes the findings from first-in-human clinical trials of SNAs in solid tumors, describes the most recent preclinical efforts to rationally design next-generation multimodal SNA architectures, and provides an outlook on future efforts to maximize the anti-neoplastic activity of the SNA platform. |
format | Online Article Text |
id | pubmed-8996871 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89968712022-04-12 Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer—From Bench to Bedside Mahajan, Akanksha S. Stegh, Alexander H. Cancers (Basel) Review SIMPLE SUMMARY: Nanotechnology enables new ways to diagnose and treat cancer. Nanomedicines can increase payload concentration at the disease site, reduce toxicity, and enhance therapeutic effects compared to drugs in their “free” form. Spherical Nucleic Acids (SNAs) emerged as a new class of oligonucleotide nanotherapeutics that are currently being explored as gene-regulatory and immunostimulatory architectures to overcome drug resistance and immunosuppression in solid tumors. This review highlights seminal studies that identified SNAs as a powerful platform for gene regulation, the activation of innate immunity, and the development of next-generation cancer vaccines, discusses recent efforts to translate fundamental discovery from the laboratory into the clinic, and provides an outlook on future research aimed at harnessing the full therapeutic potential of the SNA platform. ABSTRACT: Spherical Nucleic Acids (SNAs) emerged as a new class of nanotherapeutics consisting of a nanoparticle core densely functionalized with a shell of radially oriented synthetic oligonucleotides. The unique three-dimensional architecture of SNAs protects the oligonucleotides from nuclease-mediated degradation, increases oligonucleotide bioavailability, and in the absence of auxiliary transfection agents, enables robust uptake into tumor and immune cells through polyvalent association with cell surface pattern recognition receptors. When composed of gene-regulatory small interfering (si)RNA or immunostimulatory DNA or RNA oligonucleotides, SNAs silence gene expression and induce immune responses superior to those raised by the oligonucleotides in their “free” form. Early phase clinical trials of gene-regulatory siRNA-based SNAs in glioblastoma (NCT03020017) and immunostimulatory Toll-like receptor 9 (TLR9)-agonistic SNAs carrying unmethylated CpG-rich oligonucleotides in solid tumors (NCT03086278) have shown that SNAs represent a safe, brain-penetrant therapy for inhibiting oncogene expression and stimulating immune responses against tumors. This review focuses on the application of SNAs as precision cancer therapeutics, summarizes the findings from first-in-human clinical trials of SNAs in solid tumors, describes the most recent preclinical efforts to rationally design next-generation multimodal SNA architectures, and provides an outlook on future efforts to maximize the anti-neoplastic activity of the SNA platform. MDPI 2022-03-23 /pmc/articles/PMC8996871/ /pubmed/35406387 http://dx.doi.org/10.3390/cancers14071615 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Mahajan, Akanksha S. Stegh, Alexander H. Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer—From Bench to Bedside |
title | Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer—From Bench to Bedside |
title_full | Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer—From Bench to Bedside |
title_fullStr | Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer—From Bench to Bedside |
title_full_unstemmed | Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer—From Bench to Bedside |
title_short | Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer—From Bench to Bedside |
title_sort | spherical nucleic acids as precision therapeutics for the treatment of cancer—from bench to bedside |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996871/ https://www.ncbi.nlm.nih.gov/pubmed/35406387 http://dx.doi.org/10.3390/cancers14071615 |
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