Advances in Nanoparticles for Effective Delivery of RNA Therapeutics

Abstract

RNA therapeutics, including messenger RNA (mRNA) and small interfering RNA (siRNA), are genetic materials that mediate the translation of genetic direction from genes to induce or inhibit specific protein production. Although the interest in RNA therapeutics is rising globally, the absence of an effective delivery system is an obstacle to the clinical application of RNA therapeutics. Additionally, immunogenicity, short duration of protein expression, unwanted enzymatic degradation, and insufficient cellular uptake could limit the therapeutic efficacy of RNA therapeutics. In this regard, novel platforms based on nanoparticles are crucial for delivering RNAs to the targeted site to increase efficiency without toxicity. In this review, the most recent status of nanoparticles as RNA delivery vectors, with a focus on polymeric nanoparticles, peptide-derived nanoparticles, inorganic nanoparticles, and hybrid nanoparticles, is discussed. These nanoparticular platforms can be utilized for safe and effective RNA delivery to augment therapeutic effects. Ultimately, RNA therapeutics encapsulated in nanoparticle-based carriers will be used to treat many diseases and save lives.

Keywords: Biomaterials; Gene therapy; Nanomedicine; Nanoparticles; RNA delivery.

Fig. 1

Schematic diagram of mRNA delivery using nanomaterials

Fig. 2

Schematic illustrations of nanoparticles based on naturally derived polymers. a Chitosan structure, fabrication mechanisms of particles based on chitosan–nucleic acid (reproduced with permission from [24] Copyright 2019, Marine drugs). b Schematic representation of CNP-generated EVs for targeted nucleic acid delivery (reproduced with permission from [35] Copyright 2019, Nature Biomedical Engineering). c Schematic illustration of Ldlr mRNA encapsulation procedure into the exosomes (reproduced with permission from [37] Copyright 2021, Theranostics)

Fig. 3

Synthetic-polymer-based nanoparticles for improved delivery efficiency. a Preparation of mRNA/m after complexation with PEG-PGBA (mRNA/mPGBA) or PEG-PLL (mRNA/mPLL) (reproduced with permission from [39] Copyright 2020, Advanced Healthcare Materials). b Bioluminescence 24 h after inhalation of polyplexes; hDD90-118 vectors produced significantly higher radiance localized to the lung compared to hC32-118 and bPEI (p < 0.001, + SD, n = 4) (reproduced with permission from [40] Copyright 2019, Advanced Materials). c Representative images of in vivo luminescence imaging. Arrows represent naive mRNA/ PEG-PLys, NA/PEG-PLys injection site (NA: mRNA nanoassemblies) (reproduced with permission from [42] Copyright 2020, Biomaterials). d Quantitative evaluation of FLuc-mRNA expression level after intracerebroventricular administration of FLuc-mRNA/PAsp(DET/CHE) in mice (reproduced with permission from [44]. Copyright 2019, ACS Central Science)

Fig. 4

Synthetic-polymer-based nanoparticles for cancer therapy and vaccination. a Mice harboring two CT26 colon carcinoma tumors were treated intratumorally in one of the tumors with either Ox40l + Cd80/86 mRNA-CARTs or control mRNA-CARTs (Reproduced with permission from [52] Copyright 2019, Cancer Research). b Design of macrophage-targeted polymeric NPs based on poly(beta-amino ester) formulated with mRNAs encoding key regulators of macrophage polarization (Reproduced with permission from [53] Copyright 2019, Nature Communication). c Graphical abstract of polyglucin:spermidine conjugate as a carrier of an mRNA-RBD vaccine encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (reproduced with permission from [59] Copyright 2021, Vaccines). d Responsivity of PMs (PEG-PAsp(DET/GlcAm) to ATP. Gel electrophoresis was performed after incubation of PMs with several concentrations of ATP (reproduced with permission from [61] Copyright 2021, Journal of Controlled Release)

Fig. 5

mRNA delivery systems formulated with peptide-derived and inorganic nanoparticles. a Pulmonary delivery of mRNA formulations with different transfection agents (naked mRNA, PEG-KL4/mRNA, and lipoplex/mRNA). At 24 h post-administration, the lungs were isolated for bioluminescence imaging, and luciferase protein expression of lung tissues were measured (Reproduced with permission from [1] Copyright 2019, Journal of Controlled Release). b Graphical abstract of cell-penetrating peptide (CPP) PepFect 14 (PF14)-mRNA nanoparticles in models of ovarian cancer (Reproduced with permission from [67] Copyright 2019, European Journal of Pharmaceutics and Biopharmaceutics). c Illustration of the fully functionalized SeNP (Reproduced with permission from [74] Copyright 2021, Pharmaceutics). d Actual sizes of representative tumors after xenograft implantation followed by injection of 5 nM AuNP-αRNA I-5’BAX mRNA in mice (reproduced with permission from [75] Copyright 2013, PLOS ONE)

Fig. 6

Efficient mRNA delivery by hybrid nanoparticles. a The tolerability of the mRNA encapsulated in MOF-PGMA(EA) or PGMA(EA) complexes (at an N/P ratio of 1.5) in the presence of 10% FBS (reproduced with permission from [80] Copyright 2018, Chemical Communication). b Synthesis of the azobenzene-unit-containing metal–organic-framework-based nanoprobe (AMOF@MBs) (reproduced with permission from [82] Copyright 2019, Analyst). c mBim/DMP-039 complex suppressing the C26 subcutaneous xenograft model in vivo (reproduced with permission from [88] Copyright 2021, International Journal of Nanomedicine). d mRNA complexes stimulate innate immunity through PRR activation. Evaluation of PRR activation via the TLR7 and TLR3 pathways in HEK-Blue hTLR7 and HEK-Blue hTLR3 cells with mRNA formulations (reproduced with permission from [90] Copyright 2019, Biomaterials)