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      Surface engineering of lipid nanoparticles: targeted nucleic acid delivery and beyond

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          Abstract

          Harnessing surface engineering strategies to functionalize nucleic acid-lipid nanoparticles (LNPs) for improved performance has been a hot research topic since the approval of the first siRNA drug, patisiran, and two mRNA-based COVID-19 vaccines, BNT162b2 and mRNA-1273. Currently, efforts have been mainly made to construct targeted LNPs for organ- or cell-type-specific delivery of nucleic acid drugs by conjugation with various types of ligands. In this review, we describe the surface engineering strategies for nucleic acid-LNPs, considering ligand types, conjugation chemistries, and incorporation methods. We then outline the general purification and characterization techniques that are frequently used following the engineering step and emphasize the specific techniques for certain types of ligands. Next, we comprehensively summarize the currently accessible organs and cell types, as well as the other applications of the engineered LNPs. Finally, we provide considerations for formulating targeted LNPs and discuss the challenges of successfully translating the “proof of concept” from the laboratory into the clinic. We believe that addressing these challenges could accelerate the development of surface-engineered LNPs for targeted nucleic acid delivery and beyond.

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          Most cited references133

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          Doxil®--the first FDA-approved nano-drug: lessons learned.

          Doxil®, the first FDA-approved nano-drug (1995), is based on three unrelated principles: (i) prolonged drug circulation time and avoidance of the RES due to the use of PEGylated nano-liposomes; (ii) high and stable remote loading of doxorubicin driven by a transmembrane ammonium sulfate gradient, which also allows for drug release at the tumor; and (iii) having the liposome lipid bilayer in a "liquid ordered" phase composed of the high-T(m) (53 °C) phosphatidylcholine, and cholesterol. Due to the EPR effect, Doxil is "passively targeted" to tumors and its doxorubicin is released and becomes available to tumor cells by as yet unknown means. This review summarizes historical and scientific perspectives of Doxil development and lessons learned from its development and 20 years of its use. It demonstrates the obligatory need for applying an understanding of the cross talk between physicochemical, nano-technological, and biological principles. However, in spite of the large reward, ~2 years after Doxil-related patents expired, there is still no FDA-approved generic "Doxil" available. Copyright © 2012 Elsevier B.V. All rights reserved.
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            Central dogma of molecular biology.

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              Selective ORgan Targeting (SORT) nanoparticles for tissue specific mRNA delivery and CRISPR/Cas gene editing

              CRISPR/Cas gene editing and messenger RNA (mRNA)-based protein replacement therapy hold tremendous potential to effectively treat disease-causing mutations with diverse cellular origin. However, it is currently impossible to rationally design nanoparticles that selectively target specific tissues. Here, we report a strategy termed Selective ORgan Targeting (SORT) wherein multiple classes of lipid nanoparticles (LNPs) are systematically engineered to exclusively edit extrahepatic tissues via addition of a supplemental SORT molecule. Lung-, spleen-, and liver-targeted SORT LNPs were designed to selectively edit therapeutically relevant cell types including epithelial cells, endothelial cells, B cells, T cells, and hepatocytes. SORT is compatible with multiple gene editing techniques, including mRNA, Cas9 mRNA / sgRNA, and Cas9 ribonucleoprotein (RNP) complexes, and is envisioned to aid development of protein replacement and gene correction therapeutics in targeted tissues.
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                Author and article information

                Contributors
                Journal
                Biophys Rep
                Biophys Rep
                BR
                Biophysics Reports
                Biophysics Reports Editorial Office (Beijing China )
                2364-3439
                2364-3420
                31 October 2023
                : 9
                : 5
                : 255-278
                Affiliations
                [1 ] State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
                [2 ] Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China
                [3 ] Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
                [4 ] University of Chinese Academy of Sciences, Beijing 100049, China
                Author notes
                Article
                br-9-5-255
                10.52601/bpr.2023.230022
                10951480
                38516300
                e1d57682-8a6f-477e-bdc5-f75409bb5669
                © The Author(s) 2023

                This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 19 October 2023
                : 28 November 2023
                Categories
                Invited Review

                lipid nanoparticles,nucleic acid delivery,surface engineering,targeted delivery

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