bims-novged 2023-12-31 papers

Macromol Biosci. 2023 Dec 27. e2300362

Recent Advances in Engineering Carriers for siRNA Delivery.

Chengbin Yang, Zheng-Ian Lin, Xinmeng Zhang, Zhourui Xu, Gaixia Xu, Yu-Min Wang, Tzu-Hsien Tsai, Pei-Wen Cheng, Wing-Cheung Law, Ken-Tye Yong, Chih-Kuang Chen.

RNA interference (RNAi) technology has been a promising treatment strategy for combating intractable diseases. However, the applications of RNAi in clinical were hampered by extracellular and intracellular barriers. To overcome these barriers, various siRNA delivery systems have been developed in the past two decades. The first approved RNAi therapeutic, Patisiran (ONPATTRO™) using lipids as the carrier, for the treatment of amyloidosis is one of the most important milestones. This has greatly encouraged researchers to work on creating new functional siRNA carriers. In this review, we summarized the recent advances in siRNA carriers consisting of lipids, polymers, and polymer-modified inorganic particles for cancer therapy. Representative examples are presented to show the structural design of the carriers in order to overcome the delivery hurdles associated with RNAi therapies. Finally, the existing challenges and future perspective for developing RNAi as a clinical modality will be discussed and proposed. We believe that the addressed contributions in this review will promote the development of siRNA delivery systems for future clinical applications. This article is protected by copyright. All rights reserved.

Keywords: cationic natural polymers; cationic synthetic polymers; gene therapy; lipids; polymer-modified inorganic nanoparticles; siRNA delivery

DOI: https://doi.org/10.1002/mabi.202300362

Curr Opin Biotechnol. 2023 Dec 27. pii: S0958-1669(23)00151-9. [Epub ahead of print]85 103041

Biological recognition and cellular trafficking of targeted RNA-lipid nanoparticles.

Oscar Escalona-Rayo, Panagiota Papadopoulou, Bram Slütter, Alexander Kros.

Lipid nanoparticles (LNPs) have unlocked the potential of ribonucleic acid (RNA) therapeutics and vaccines. Production and large-scale manufacturing methods for RNA-LNPs have been established and rapidly accelerate. Despite this, basic research on LNPs is still required, due to their high assembly complexity and fairly new development, including research on lipid organization, transfection optimization, and in vivo behavior. Understanding fundamental aspects of LNPs that is, how lipid composition and physicochemical properties affect their biodistribution, cell recognition, and transfection, could propel their clinical development and facilitate overcoming current challenges. Herein, we review recent developments in the field of LNP technology and summarize the main findings focusing on nano-bio interactions.

DOI: https://doi.org/10.1016/j.copbio.2023.103041

Int J Nanomedicine. 2023 ;18 7785-7801

Liver-Specific Ionizable Lipid Nanoparticles Mediated Efficient RNA Interference to Clear "Bad Cholesterol".

Chuangjia Huang, Yu Zhang, Jianfen Su, Xiaoling Guan, Sheng Chen, Xiaowei Xu, Xiaohua Deng, Lingmin Zhang, Jionghua Huang.

Background: High-level low-density lipoprotein cholesterol (LDL-C) plays a vital role in the development of atherosclerotic cardiovascular disease. Low-density lipoprotein receptors (LDLRs) are scavengers that bind to LDL-C in the liver. LDLR proteins are regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9), which mediates the degradation of LDLR and adjusts the level of the plasma LDL-C. The low expression of PCSK9 leads to the up-regulation of liver LDLRs and the reduction of plasma LDL-C. Hepatocytes are attractive targets for small interfering RNA (siRNA) delivery to silence Pcsk9 gene, due to their significant role in LDL-C regulation.
Methods: Here, a type of liver-specific ionizable lipid nanoparticles is developed for efficient siRNA delivery. This type of nanoparticles shows high stability, enabling efficient cargo delivery specifically to hepatocytes, and a membrane-active polymer that reversibly masks activity until an acidic environment is reached.
Results: Significantly, the siPcsk9 (siRNA targeting to Pcsk9)-loaded nanoparticles (GLP) could silence 90% of the Pcsk9 mRNA in vitro. In vivo study showed that the improved accumulation of GLP in the liver increased LDLR level by 3.35-fold and decreased plasma LDL-C by 35%.
Conclusion: GLP has shown a powerful effect on reducing LDL-C, thus providing a potential therapy for atherosclerotic cardiovascular disease.

Keywords: PCSK9; bad cholesterol; ionizable lipid nanoparticles; liver-specific delivery; small interfering RNA

DOI: https://doi.org/10.2147/IJN.S434908

Trends Immunol. 2023 Dec 22. pii: S1471-4906(23)00257-0. [Epub ahead of print]

The potential of mRNA vaccines in cancer nanomedicine and immunotherapy.

Shulin Pan, Rangrang Fan, Bo Han, Aiping Tong, Gang Guo.

Owing to their outstanding performance against COVID-19, mRNA vaccines have brought great hope for combating various incurable diseases, including cancer. Differences in the encoded proteins result in different molecular and cellular mechanisms of mRNA vaccines. With the rapid development of nanotechnology and molecular medicine, personalized antigen-encoding mRNA vaccines that enhance antigen presentation can trigger effective immune responses and prevent off-target toxicities. Herein, we review new insights into the influence of encoded antigens, cytokines, and other functional proteins on the mechanisms of mRNA vaccines. We also highlight the importance of delivery systems and chemical modifications for mRNA translation efficiency, stability, and targeting, and we discuss the potential problems and application prospects of mRNA vaccines as versatile tools for combating cancer.

Keywords: cancer; delivery systems; immunotherapy; mRNA vaccine; nanomedicine

DOI: https://doi.org/10.1016/j.it.2023.11.003

Br J Dermatol. 2023 Dec 27. pii: ljad528. [Epub ahead of print]

Topical gene editing therapeutics using lipid nanoparticles: "gene creams" for genetic skin diseases?

Ina Guri-Lamce, Yara AlRokh, Youngah Kim, Ruhina Maeshima, Carina Graham, Stephen L Hart, John A McGrath, Joanna Jacków-Malinowska.

Patients living with inherited skin diseases have benefitted from recent advances in DNA sequencing technologies that provide new or improved diagnostics. However, developing and delivering new treatments for the "genodermatoses" remains challenging. The goal of creating topical preparations that can recover the inherent gene pathology remains largely aspirational. However, recent progress in two fields, the chemistry of topical delivery formulations (lipid nanoparticles) and the molecular biology of gene repair (CRISPR-Cas9, base and prime editing), now presents new opportunities to address that unmet need. In this review, we discuss how lipid nanoparticle delivery vehicles could be used to deliver gene editing tools to formulate topical "gene creams" suitable for the treatment of genodermatoses. We summarise the historical landscape of topical therapeutics and advances in gene editing which may herald an era of new therapies for patients with inherited skin disorders.

DOI: https://doi.org/10.1093/bjd/ljad528