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Review
.2019 Aug 28:458:102-112.
doi: 10.1016/j.canlet.2019.04.040. Epub 2019 May 14.

Nanoparticles for nucleic acid delivery: Applications in cancer immunotherapy

Affiliations
Review

Nanoparticles for nucleic acid delivery: Applications in cancer immunotherapy

Alvin J Mukalel et al. Cancer Lett..

Abstract

Immunotherapy has recently emerged as a powerful tool for cancer treatment. Early clinical successes from cancer immunotherapy have led to a growing list of FDA approvals, and many new therapies are in clinical and preclinical development. Nucleic acid therapeutics, including DNA, mRNA, and genome editing systems, hold significant potential as a form of immunotherapy due to its robust use in cancer vaccination, adoptive T-cell therapy, and gene regulation. However, these therapeutics must overcome numerous delivery obstacles to be successful, including rapid in vivo degradation, poor uptake into target cells, required nuclear entry, and potential in vivo toxicity in healthy cells and tissues. Nanoparticle delivery systems have been engineered to overcome several of these barriers as a means to safely and effectively deliver nucleic acid therapeutics to immune cells. In this Review, we discuss the applications of nucleic acid therapeutics in cancer immunotherapy, and we detail how nanoparticle platforms have been designed to deliver mRNA, DNA, and genome editing systems to enhance the potency and safety of these therapeutics.

Keywords: CRISPR; DNA; Drug delivery; Gene editing; Nanotechnology; Oncology; mRNA.

Copyright © 2019 Elsevier B.V. All rights reserved.

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Conflict of interest statement

Competing Interests

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
The role of non-viral vectors in overcoming extracellular and intracellular barriers for nucleic acid delivery. In circulation, non-viral vectors need to protect nucleic acids from serum endo- and exonucleases, evade immune detection, and avoid non-specific protein interactions within the blood. Further, vectors must avoid renal clearance (achieved through size modulation), while also promoting extravasation from the blood and into target tissues, upon which they promote cellular uptake and localization into the cytosol or nucleus. Adapted from [24].
Figure 2
Figure 2
Chemical structures of common non-viral vectors used for nucleic acid delivery.A. Common lipids used for liposomal formulations including DOTMA, DOSPA, DOTAP, DMRIE and DC-cholesterol, which are used to condense and encapsulate nucleic acids. Structurally, cationic lipids are defined as having a cationic head group, linker region, and hydrophobic tails.B. Ionizable LNP formulations are comprised of four components: ionizable lipids, such as C12– 200, phospholipids (DOPE, DSPC), cholesterol, and lipid-anchored PEG.C. Cationic polymers and biopolymers used as vectors for nucleic acid delivery. PEI and PLL were two of the initial vectors used for DNA delivery but are faced with safety (PEI) and efficacy (PLL) concerns. PBAEs and pDMAEMA are newer polymer vectors developed for nucleic acid delivery with improved safety and efficacy. Panels A and B are adapted from [24].
Figure 3
Figure 3
NP delivery platforms used for gene therapies.A. PBAE polymer functionalized with an MTAS-NLS peptide was used to condense CAR-encoding plasmid DNA. In this application, an anti-CD3e-poly(glutamic acid) (PGA) conjugate was adsorbed to the surface of the PBAE core to enable T-cell targeting andin situ generation of CAR T-cells. Adapted from [81].B. PBAE polymer used to deliver a Stimulator of Interferon Receptor Genes (STING) antagonizing cyclic dinucleotide (CDN) intratumorally in combination with a PD-1 blocking antibody and demonstrated potent inhibition of tumor growth. Adapted from [83].C. A biodegradable ionizable lipid was used to co-deliver a modified sgRNA and Cas9 mRNA that achieved potent gene editing in the liver for 12 weeks. sgRNA was modified with phosphothiorate bonds at both ends of the strand (indicated by *) and 2’-O-methylation of nucleotides (shown in red). Adapted from [126].D. Multilamellar ionizable lipid NPs generated potent CD8 T-cell activation upon antigen delivery and were used to deliver tumor antigens gp100 and TRP2 that led to tumor shrinkage and elongated survival in a B16F10 melanoma mouse model. Adapted from [49].
Figure 4
Figure 4
Methods for genome editing systems. Zinc-finger nucleases (ZFN), transcription activator-like nuclease (TALEN), or CRISPR-Cas systems can be delivered with non-viral delivery platforms. These gene editing systems can edit mammalian genomes by introducing double stranded breaks in a highly specific, sequence-dependent manner. Repair occurs through non-homologous end-joining or by homology-directed repair. Adapted from [112].
Figure 5
Figure 5
Sites of therapeutic intervention for NPs to generate anti-tumor immune responses in solid tumors. Anti-tumor immune responses result from the presentation of tumor-associated antigens (TAAs), stimulating protective T-cell responses, and overcoming the immunosuppressive tumor microenvironment (TME). NPs can be used to activate these pathways to successfully deliver immunotherapeutics to solid tumors by: (1) enhancing delivery of nucleic acids encoding TAAs to improve delivery to antigen presenting cells for immune activation; (2) delivering nucleic acids to T-cells to promote their survival, proliferation, and anti-tumor phenotypes; and (3) alleviating the immunosuppressive signaling within the tumor microenvironment. Figure adapted from [141]
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