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Natural Polysaccharides for siRNA Delivery: Nanocarriers Based on Chitosan, Hyaluronic Acid, and Their Derivatives

Serrano-Sevilla, Inés, Artiga, Álvaro, Mitchell, Scott G., De Matteis, Laura, de la Fuente, Jesús M.·2019·Molecules
DOI 10.3390/molecules24142570PMC PMC6680562
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Abstract

Natural polysaccharides are frequently used in the design of drug delivery systems due to their biocompatibility, biodegradability, and low toxicity. Moreover, they are diverse in structure, size, and charge, and their chemical functional groups can be easily modified to match the needs of the final application and mode of administration. This review focuses on polysaccharidic nanocarriers based on chitosan and hyaluronic acid for small interfering RNA (siRNA) delivery, which are highly positively and negatively charged, respectively. The key properties, strengths, and drawbacks of each polysaccharide are discussed. In addition, their use as efficient nanodelivery systems for gene silencing applications is put into context using the most recent examples from the literature. The latest advances in this field illustrate effectively how chitosan and hyaluronic acid can be modified or associated with other molecules in order to overcome their limitations to produce optimized siRNA delivery systems with promising in vitro and in vivo results.

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Scheme 1 Challenges related with in vivo small interfering RNA (siRNA) delivery and solutions provided by the use of nanocarriers to overcome the problems of free siRNA delivery.
Scheme 1 Challenges related with in vivo small interfering RNA (siRNA) delivery and solutions provided by the use of nanocarriers to overcome the problems of free siRNA delivery.CC BY · PubMed Central
Figure 1 Chemical structures of chitosan (A) and hyaluronic acid (B).
Figure 1 Chemical structures of chitosan (A) and hyaluronic acid (B).CC BY · PubMed Central
Figure 2 Types of polysaccharide-based nanoparticles depending on their components, the interactions between them and their final structure: polyelectrolyte complex (A); nanogel (B); and polymeric micelle (C).
Figure 2 Types of polysaccharide-based nanoparticles depending on their components, the interactions between them and their final structure: polyelectrolyte complex (A); nanogel (B); and polymeric micelle (C).CC BY · PubMed Central
Figure 3 Schematic illustrations of the preparation of modified chitosan nanocarriers and their antitumor efficacies overcoming the systemic and intracellular delivery barriers for the synergistic delivery of two siRNAs. The nanoparticles were synthesized using polyethylene glycol (PEG) and mannose doubly modified trimethyl chitosan (PEG = MT) along with citraconic anhydride grafted poly (allylamine hydrochloride) (PC). Adapted from [90] with permission from Elsevier.
Figure 3 Schematic illustrations of the preparation of modified chitosan nanocarriers and their antitumor efficacies overcoming the systemic and intracellular delivery barriers for the synergistic delivery of two siRNAs. The nanoparticles were synthesized using polyethylene glycol (PEG) and mannose doubly modified trimethyl chitosan (PEG = MT) along with citraconic anhydride grafted poly (allylamine hydrochloride) (PC). Adapted from [90] with permission from Elsevier.CC BY · PubMed Central
Figure 4 Schematic illustration of co-delivery of VEGF and Bcl-2 siRNAs using the dual-nanoparticle (dual-NP) system. Dual-poly-siRNA (A) was incorporated in the thiolated glycol chitosan (tGC) to form nanoparticle structures (dual-NPs) through the charge-charge interaction and chemical crosslinking (B). Adapted from [85] with permission from Elsevier.
Figure 4 Schematic illustration of co-delivery of VEGF and Bcl-2 siRNAs using the dual-nanoparticle (dual-NP) system. Dual-poly-siRNA (A) was incorporated in the thiolated glycol chitosan (tGC) to form nanoparticle structures (dual-NPs) through the charge-charge interaction and chemical crosslinking (B). Adapted from [85] with permission from Elsevier.CC BY · PubMed Central
Figure 5 Structure of a cholesterol-grafted chitosan micelle loaded with siRNA and curcumin for co-delivery. Adapted from [96] with permission from Elsevier.
Figure 5 Structure of a cholesterol-grafted chitosan micelle loaded with siRNA and curcumin for co-delivery. Adapted from [96] with permission from Elsevier.CC BY · PubMed Central
Figure 6 Scheme of the formation of covalent crosslinked polyplex hyaluronic acid (HA)- polyethylenimine (PEI)/siRNA (A) and illustration of serum tolerance of covalently crosslinked HA-PEI/siRNA versus poor serum stability of non-covalently crosslinked HA-PEI/siRNA (B). Reproduced from [150] with permission from American Chemical Society.
Figure 6 Scheme of the formation of covalent crosslinked polyplex hyaluronic acid (HA)- polyethylenimine (PEI)/siRNA (A) and illustration of serum tolerance of covalently crosslinked HA-PEI/siRNA versus poor serum stability of non-covalently crosslinked HA-PEI/siRNA (B). Reproduced from [150] with permission from American Chemical Society.CC BY · PubMed Central
Figure 7 In vivo siRNA delivery efficiency of adelivery system with a redox-sensitive cationic inner core and detachable hyaluronic acid (HA) crosslinked outer shell, named as HA-PSR, for simultaneous delivery of siRNA and paclitaxel (PTX) within tumour cells. HA-PCR corresponds to a version of the delivery system with a non-redox-sensitive core. Gene silencing was assessed through mRNA quantification and biodistribution was analyzed using fluorescently labeled siRNA (Cy5-siRNA) loaded into fluorescently labeled nanoparticles (HA-C6PCR or HA-C6PSR). Plk1 mRNA expression at different si-Plk1 concentrations (A) or scrambled siRNA (si-con) concentrations (B) determined by qRT-PCR. (C) In vivo fluorescent imaging of A549 tumour-bearing nude mice after intravenous injection of C6/Cy5-siRNA co-loaded HA-PSR/HA-PCR nanoparticles with or without pre-injection of free HA. (D) Ex vivo Cy5 fluorescence imaging of the tumour and normal tissues of the A549 tumour-bearing nude mice at 24 h post-injection. 1, tumour; 2, heart; 3, spleen; 4, liver; 5, kidney; and 6, lung. (E) Region-of-interest (ROI) analysis of Cy5 fluorescent signals from the tumours and normal tissues. *p < 0.05. Adapted from [142] with permission from Elsevier.
Figure 7 In vivo siRNA delivery efficiency of adelivery system with a redox-sensitive cationic inner core and detachable hyaluronic acid (HA) crosslinked outer shell, named as HA-PSR, for simultaneous delivery of siRNA and paclitaxel (PTX) within tumour cells. HA-PCR corresponds to a version of the delivery system with a non-redox-sensitive core. Gene silencing was assessed through mRNA quantification and biodistribution was analyzed using fluorescently labeled siRNA (Cy5-siRNA) loaded into fluorescently labeled nanoparticles (HA-C6PCR or HA-C6PSR). Plk1 mRNA expression at different si-Plk1 concentrations (A) or scrambled siRNA (si-con) concentrations (B) determined by qRT-PCR. (C) In vivo fluorescent imaging of A549 tumour-bearing nude mice after intravenous injection of C6/Cy5-siRNA co-loaded HA-PSR/HA-PCR nanoparticles with or without pre-injection of free HA. (D) Ex vivo Cy5 fluorescence imaging of the tumour and normal tissues of the A549 tumour-bearing nude mice at 24 h post-injection. 1, tumour; 2, heart; 3, spleen; 4, liver; 5, kidney; and 6, lung. (E) Region-of-interest (ROI) analysis of Cy5 fluorescent signals from the tumours and normal tissues. *p < 0.05. Adapted from [142] with permission from Elsevier.CC BY · PubMed Central
Figure 8 Effect of the combination of the downregulation of two antiapoptotic genes (survivin and bcl-2) and cisplatin treatment. Comparison of the antitumor efficacy of cisplatin-treated mice with survivin + cisplatin-treated mice, cisplatin-treated mice with bcl-2 + cisplatin-treated mice, cisplatin-treated mice with CTL siRNA (non-targeting control siRNA) + cisplatin-treated mice, cisplatin-treated mice with survivin + cisplatin, and survivin + bcl-2 + cisplatin-treated mice. Reproduced [149] from with permission from Elsevier.
Figure 8 Effect of the combination of the downregulation of two antiapoptotic genes (survivin and bcl-2) and cisplatin treatment. Comparison of the antitumor efficacy of cisplatin-treated mice with survivin + cisplatin-treated mice, cisplatin-treated mice with bcl-2 + cisplatin-treated mice, cisplatin-treated mice with CTL siRNA (non-targeting control siRNA) + cisplatin-treated mice, cisplatin-treated mice with survivin + cisplatin, and survivin + bcl-2 + cisplatin-treated mice. Reproduced [149] from with permission from Elsevier.CC BY · PubMed Central

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Metadata

Authors
Serrano-Sevilla, I., Artiga, Á., Mitchell, S. G., De Matteis, L., & de la Fuente, J. M.
Venue
Molecules
Publisher
MDPI AG
Published
2019-07-15
Volume
24
Issue
14
Pages
2570
ISSN
1420-3049
DOI
10.3390/molecules24142570
PMC
PMC6680562
Cited by
148
References
4
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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CoChat. (2026). Citation check: Natural Polysaccharides for siRNA Delivery: Nanocarriers Based on Chitosan, Hyaluronic Acid, and Their Derivatives. https://app.cochat.ai/papers/10.3390/molecules24142570
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Serrano-Sevilla, I., Artiga, Á., Mitchell, S. G., De Matteis, L., & de la Fuente, J. M. (2019). Natural Polysaccharides for siRNA Delivery: Nanocarriers Based on Chitosan, Hyaluronic Acid, and Their Derivatives. Molecules. https://doi.org/10.3390/molecules24142570