mRNA nanodelivery systems: targeting strategies and administration routes

(2023) 27:90 Yuan et al. Biomaterials Research https://doi.org/10.1186/s40824-023-00425-3 Biomaterials Research Open Access REVIEW mRNA nanodelivery systems: targeting strategies and administration routes Mujie Yuan1†, Zeyu Han1†, Yan Liang2, Yong Sun2, Bin He3, Wantao Chen4* and Fan Li1* Abstract With the great success of coronavirus disease (COVID-19) messenger ribonucleic acid (mRNA) vaccines, mRNA therapeutics have gained significant momentum for the prevention and treatment of various refractory diseases. To function efficiently in vivo and overcome clinical limitations, mRNA demands safe and stable vectors and a reasonable administration route, bypassing multiple biological barriers and achieving organ-specific targeted delivery of mRNA. Nanoparticle (NP)-based delivery systems representing leading vector approaches ensure the successful intracellular delivery of mRNA to the target organ. In this review, chemical modifications of mRNA and various types of advanced mRNA NPs, including lipid NPs and polymers are summarized. The importance of passive targeting, especially endogenous targeting, and active targeting in mRNA nano-delivery is emphasized, and different cellular endocytic mechanisms are discussed. Most importantly, based on the above content and the physiological structure characteristics of various organs in vivo, the design strategies of mRNA NPs targeting different organs and cells are classified and discussed. Furthermore, the influence of administration routes on targeting design is highlighted. Finally, an outlook on the remaining challenges and future development toward mRNA targeted therapies and precision medicine is provided. Keywords mRNA, Nanodelivery systems, Targeting, Administration routes † Mujie Yuan and Zeyu Han contributed equally to this work. *Correspondence: Wantao Chen Fan Li Full list of author information is available at the end of the article © The Author(s) 2023. Open Access 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yuan et al. Biomaterials Research (2023) 27:90 Page 2 of 48 Graphical Abstract Introduction In the 1990s, Wolff et al. found for the first time that injecting in vitro transcription (IVT) messenger ribonucleic acid (mRNA) could produce proteins successfully in mice [1]. Since this discovery, the prospective of therapy based on mRNA has come into public view (Fig. 1). Benefited from the demand for coronavirus disease (COVID19) vaccines, mRNA therapy is evolving rapidly [2, 3]. As a preventive or therapeutic drug, mRNA produces functional proteins with almost all known sequences, favorable safety, and effectiveness at any target, which has broad prospects in the fields of precision and personalized medicine [4–6]. However, due to its single-stranded structure, naked mRNA is destabilized in vivo and easily degraded by ribonuclease (RNase) [7]. Moreover, it is hard for a negatively charged mRNA macromolecule to cross the host cell membrane, which is also negatively charged, resulting in inefficient cell permeation [8]. To address these challenges, the rapid development of mRNA engineering technologies, including chemical modification, and the use of reasonable carriers to protect mRNA from RNase degradation and assist with intracellular mRNA delivery. Nanoparticle (NP)-based platforms are widely considered the most promising potential mRNA drug delivery system (DDS) owing to its ability to alter the properties through controllable and simple chemical synthesis, resulting in enhanced mRNA-binding affinity and delivery potency [11]. The premise of mRNA therapy is to deliver mRNA to specific organs and cells accurately. However, the physiological structures and microenvironment vary considerably in different organs and cells, which challenges the precise delivery of mRNA NPs. Moreover, the in vivo biological barriers, the rapid clearance by mononuclear phagocytic system (MPS), and suboptimal biodistribution also influence the delivery of mRNA NPs [12]. To address these issues, researchers designed targetable mRNA NPs and successfully delivered mRNA to organs and cells through rational administration routes and specific design strategies. For instance, Lokugamage et al. [13] designed mRNA NPs targeting the lungs via Yuan et al. Biomaterials Research (2023) 27:90 Page 3 of 48 Fig. 1 Timeline of some key discoveries for mRNA therapeutics development. Reproduced with permission [6]. Copyright 2017, Macmillan Publishers. Reproduced with permission [9]. Copyright 2023, American Chemical Society. Reproduced with permission [10]. Copyright 2022, Springer Nature. Reproduced with permission [5]. Copyright 2021, Springer Nature intranasal administration for protection against influenza A virus. Due to the design of high molarity polyethylene glycol (PEG) and cationic helper lipids, mRNA NPs overcame the physiological barriers to reach the lung epithelial cells and released mRNA to prevent influenza A virus infection. Similarly, Yang et al. [14] designed hepatocyte nuclear factor 4 alpha (HNF4A)-mRNA NPs to target hepatocytes via intravenous administration based on the characteristics of abundant blood flow and endothelial fenestrations in liver. This brings new hope to the treatment of liver fibrosis. Typically, vaccine administration routes, along with physiological characteristics of the target, affect the design of targeting strategies and mainly depend on the location and physiological characteristics of target organs/ cells. The different targeting strategies of mRNA NPs include passive, active, and endogenous targeting, which has shown variable influence on the distribution of mRNA NPs in vivo on systemic administration [15]. Passive targeting is usually affected by the physicochemical properties of NPs such as size, zeta potential, and pKa, while active targeting is mainly achieved by introducing target-specific ligands like antibodies and small molecules [16]. Notably, for endogenous targeting, the biomolecular co (...truncated)