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Review
. 2023 Jul 27:11:1208547.
doi: 10.3389/fbioe.2023.1208547. eCollection 2023.

Applications of nanotechnologies for miRNA-based cancer therapeutics: current advances and future perspectives

Affiliations
Review

Applications of nanotechnologies for miRNA-based cancer therapeutics: current advances and future perspectives

Luis Alberto Bravo-Vázquez et al. Front Bioeng Biotechnol. .

Abstract

MicroRNAs (miRNAs) are short (18-25 nt), non-coding, widely conserved RNA molecules responsible for regulating gene expression via sequence-specific post-transcriptional mechanisms. Since the human miRNA transcriptome regulates the expression of a number of tumor suppressors and oncogenes, its dysregulation is associated with the clinical onset of different types of cancer. Despite the fact that numerous therapeutic approaches have been designed in recent years to treat cancer, the complexity of the disease manifested by each patient has prevented the development of a highly effective disease management strategy. However, over the past decade, artificial miRNAs (i.e., anti-miRNAs and miRNA mimics) have shown promising results against various cancer types; nevertheless, their targeted delivery could be challenging. Notably, numerous reports have shown that nanotechnology-based delivery of miRNAs can greatly contribute to hindering cancer initiation and development processes, representing an innovative disease-modifying strategy against cancer. Hence, in this review, we evaluate recently developed nanotechnology-based miRNA drug delivery systems for cancer therapeutics and discuss the potential challenges and future directions, such as the promising use of plant-made nanoparticles, phytochemical-mediated modulation of miRNAs, and nanozymes.

Keywords: MicroRNAs; cancer; gene regulation; nanoparticles; targeted delivery; therapeutics.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic representation of miRNA biogenesis. In the nucleus, RNA Pol II transcribes miRNAs, which are then folded into a secondary hairpin shape and stem-loop structure called pri-miRNA. Afterward, such structure is cleaved by the RNases II DROSHA and DGCR8, to generate pre-miRNAs. Subsequently, XPO5 transports pre-miRNAs to the cytoplasm, where DICER1 processes them to form a miRNA duplex, composed of a guide and passenger strand. The latter is degraded while the guide strand binds to AGO in order to form the RISC. Finally, mature miRNAs are able to regulate gene expression at the post-transcriptional level by mRNA cleavage or translation inhibition. Dysregulation of endogenous miRNA expression can contribute to the progression of cancer. Hence, therapeutic approaches employing NPs provide an opportunity for targeted delivery of antagomirs or mimics to the cytoplasm. This targeted delivery allows for the inhibition of endogenous miRNAs or restoration of miRNA function, respectively, aiming to restore miRNA levels and promote a healthy state.
FIGURE 2
FIGURE 2
Advantages of the NP-mediated delivery of miRNA-based drugs. Nucleic acids, as well as the cell membrane, are negatively charged, which makes cell internalization of naked miRNAs a challenge. Cationic NPs envelop miRNAs in a positively-charged shield which improves cellular uptake. Moreover, the addition of target ligands in the outer layer of NPs can enhance selectivity and reduce off-target effects. Furthermore, controlled release of the therapeutic cargo can be achieved when the NPs are in contact with stimuli such as specific enzymes, ultrasound, magnetic fields and temperature, to name a few. Additionally, nanoencapsulation boosts miRNA stability by protecting them from nuclease degradation and inhibiting undesired immune activation through the implementation of PEG-based coating.
FIGURE 3
FIGURE 3
Schematic representation of the therapeutic effects of nanotechnology-mediated miRNA therapeutics on breast cancer. (A) miR-34a-mimic and anti-miR-10b were co-delivered into breast cancer cells using MSNs as delivery vehicles, triggering tumor growth inhibition and metastasis delay. (B) miR-21 inhibitor and DOX drug were co-delivered into breast tumors using CSTDs built with a generation 3 adamantane and a generation 5 cyclodextrin, which caused anti-migratory effect, and apoptosis of breast cancer cells. Additionally, this therapy produced the upregulation of Caspase-3, PTEN, PDCD4, and p53; and the downregulation of miR-21. (C) miR27b was conjugated with fullerenes and released into PTX-resistant breast cancer cells, which allowed the regulation of tumor growth, suppression of metastasis, and enhanced apoptosis. Further, this treatment downregulated CREB1 and CYP1B1 expression. (D) miR-34a and DTX were delivered into breast cancer cells employing hybrid lipopolymeric nanoplexes mainly composed by a polycarbonate backbone coupled with cholesterol, lactic acid, and folate. This treatment induced the inhibition metastasis and angiogenesis, increased apoptosis, caused the downregulation of Ki-67 and BCL2, and upregulation of BAX. (E) miR-22-3p transfected into breast tumors through SLNP inhibited tumor growth, metastasis, and migration. Moreover, eEF2K became downregulated. (F) Ce6-anti-miR-21 and Ce6-anti-miR-155 were co-delivered into breast cancer cell lines employing ZIF-90, a nanoparticle constructed with zinc ions and imidazole-2-carboxaldehyde. Consequently, tumor growth and metastasis were reduced. (G) LTX-315, Mel, and miR-34a were synthesized with a polyelectrolyte nanocarrier composed of a CS-polyglutamic acid core protected by a polyethyleneimine shell and FA ligands. This combination of molecules caused the targeted breast cancerous cells to undergo apoptosis. (H) miR-206 was loaded into PEG-conjugated AuNPs, and transported to breast cancer cells, triggering apoptosis, downregulating NOTCH3, BCL2, and upregulating BAX.
FIGURE 4
FIGURE 4
Impact of nanotechnology-mediated miRNA therapeutics in lung cancer. (A) miR-29a-3p was delivered into lung cancer cells employing LPX and CPT-Exo. DOTAP was conjugated with cholesterol to surround miR-29a-3p in the LPX nanoparticle. Meanwhile, CPT-Exo nanoconjugate consisted of miR-29a-3p protected by cisplatin-elicited exosomes. In both cases, decreased metastasis and downregulation of Colla1 were noticed. (B) miR-126 was liberated into lung cancerous cells using FA-CS as a nano vehicle. This triggered apoptosis of damaged cells, downregulation of EGFL7, CASP9, and BAX; as well as upregulation of ATG5 and BECN1. (C) miR-148b was chemically attached to iron oxide nanoparticles through the Diels–Alder linker, and delivered into lung tumors, resulting in apoptosis, suppression of CAMs, and a decrease of cancerous cell migration.
FIGURE 5
FIGURE 5
Clinical inferences of NP-delivered miRNA therapeutics in glioblastoma cells. (A) anti-miR-21 and miR-124 were administered into cancerous brain cells using polymeric NPs NPs coated with angiopep-2 and PEG. These miRNAs reduced cell proliferation, migration, and angiogenesis; and promoted apoptosis of brain cancer cells. Furthermore, they increased PTEN expression while decreasing RAS expression. (B) A semi-conducting polymer decorated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine and PEG liberated miR-7 inside brain tumors under PA force stimuli. This delivery triggered a reduction in tumor growth and angiogenesis. Also, it caused the apoptosis of the cancerous cells, upregulated TRAIL, and lowered the expression of XIAP. (C) miR-219 was loaded into CNPs with tripolyphosphate and transferred into glioblastoma cells. This therapy decreased metastasis, promoted apoptosis, and reduced cell migration and proliferation. ROBO1, SALL4, and EGFR were downregulated after this treatment. (D) anti-miR-21 was loaded onto the SpAcDex nanoparticle system and delivered into brain tumors, inhibiting angiogenesis and tumor growth; and stimulating apoptosis. Besides, it downregulated HIFα and VEGF, while upregulating PTEN and PDCD4. The SpAcDex nanostructure consisted of a dextran core enveloped by an acetal layer and decorated by a spermine and bradykinin ligand conjugate. Cyanine 5 served as a fluorophore marker to indicate the presence of anti-miR-21.
FIGURE 6
FIGURE 6
Future insights for nanotechnology-mediated miRNA-based therapeutics in cancer treatment. One of the key challenges in cancer treatment relies on the fact that patients commonly develop resistance to therapies such as chemotherapy and radiation, miRNAs capable of modulating this response should be exploited as therapeutic targets. Furthermore, the development of new in silico models to allow early pharmaceutical and biosafety studies of miRNA-centered nanomedicines would be highly desirable. Plant NPs, as biocompatible and cost-effective devices, should be leveraged for the delivery of artificial miRNAs along with plan viruses and plant virus-associated particles. Likewise, forthcoming studies should explore the combination of NPs with phytochemicals that modulate miRNA expression in cancer to generate innovative treatments. As well, nanozymes, being great immunomodulators, could be used in combination with miRNA-centered drugs to improve antitumor effects.

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