RNAi therapies: Expanding applications for extrahepatic diseases and overcoming delivery challenges

Jong Won Lee; Man Kyu Shim; Hyosuk Kim; Hochung Jang; Yuhan Lee; Sun Hwa Kim

doi:10.1016/j.addr.2023.115073

RNAi therapies: Expanding applications for extrahepatic diseases and overcoming delivery challenges

Adv Drug Deliv Rev. 2023 Oct:201:115073. doi: 10.1016/j.addr.2023.115073. Epub 2023 Aug 30.

Authors

Jong Won Lee¹, Man Kyu Shim², Hyosuk Kim², Hochung Jang³, Yuhan Lee⁴, Sun Hwa Kim⁵

Affiliations

¹ KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea; Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
² Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
³ Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea.
⁴ Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Accelerated Medical Innovation & Center for Nanomedicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ylee21@bwh.harvard.edu.
⁵ KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea; Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea. Electronic address: sunkim@kist.re.kr.

PMID: 37657644
DOI: 10.1016/j.addr.2023.115073

Abstract

The era of RNA medicine has become a reality with the success of messenger RNA (mRNA) vaccines against COVID-19 and the approval of several RNA interference (RNAi) agents in recent years. Particularly, therapeutics based on RNAi offer the promise of targeting intractable and previously undruggable disease genes. Recent advances have focused in developing delivery systems to enhance the poor cellular uptake and insufficient pharmacokinetic properties of RNAi therapeutics and thereby improve its efficacy and safety. However, such approach has been mainly achieved via lipid nanoparticles (LNPs) or chemical conjugation with N-Acetylgalactosamine (GalNAc), thus current RNAi therapy has been limited to liver diseases, most likely to encounter liver-targeting limitations. Hence, there is a huge unmet medical need for intense evolution of RNAi therapeutics delivery systems to target extrahepatic tissues and ultimately extend their indications for treating various intractable diseases. In this review, challenges of delivering RNAi therapeutics to tumors and major organs are discussed, as well as their transition to clinical trials. This review also highlights innovative and promising preclinical RNAi-based delivery platforms for the treatment of extrahepatic diseases.

Keywords: Clinical translation; Delivery systems; Gene delivery; Organ-specific targeting; RNA interference.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

COVID-19 Vaccines
COVID-19* / therapy
Humans
Nanoparticles* / chemistry
RNA Interference
RNA, Small Interfering
RNAi Therapeutics

Substances

RNA, Small Interfering
COVID-19 Vaccines