A ribonucleoprotein octamer for targeted siRNA delivery

Tai, Wanyi; Li, Junwei; Corey, Eva; Gao, Xiaohu

doi:10.1038/s41551-018-0214-1

Cited by 69 publications

(57 citation statements)

References 54 publications

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“…As the delivery systems of nucleic acids, the inherent features of conventional cationic materials, including associated cytotoxicity, large and heterogeneous complex sizes, and rapid clearance by the reticuloendothelial system, limited their clinical application. As such, the non‐cationic formulations, including natural proteins, polymers, cells, or liposomes, have been developed to overcome these barriers of conventional cationic materials for clinical translation. In this review, we discussed our advances in the development, improvements, and application of CLAN nanoparticles for the delivery of nucleic acids.…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

Development of “CLAN” Nanomedicine for Nucleic Acid Therapeutics

Iqbal

Shen

et al. 2019

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Nucleic acid‐based macromolecules have paved new avenues for the development of therapeutic interventions against a spectrum of diseases; however, their clinical translation is limited by successful delivery to the target site and cells. Therefore, numerous systems have been developed to overcome delivery challenges to nucleic acids. From the viewpoint of clinical translation, it is highly desirable to develop systems with clinically validated materials and controllability in synthesis. With this in mind, a cationic lipid assisted PEG‐b‐PLA nanoparticle (CLAN) is designed that is capable of protecting nucleic acids via encapsulation inside the aqueous core, and delivers them to target cells, while maintaining or improving nucleic acid function. The system is formulated from clinically validated components (PEG‐b‐PLA and its derivatives) and can be scaled‐up for large scale manufacturing, offering potential for its future use in clinical applications. Here, the development and working mechanisms of CLANs, the ways to improve its delivery efficacy, and its application in various disease treatments are summarized. Finally, a prospective for the further development of CLAN is also discussed.

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Section: Conclusion and Prospectsmentioning

confidence: 99%

Development of “CLAN” Nanomedicine for Nucleic Acid Therapeutics

Iqbal

Shen

et al. 2019

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“…[ 25–27 ] Therefore, DONs have been increasingly employed for developing novel drug delivery systems [ 28,29 ] due to their versatile designability, high solubility, and intrinsic biocompatibility. [ 30–37 ] Moreover, certain types of DONs have been proven to be readily rapidly internalized by mammalian cells despite their negatively charged surface property. [ 38 ]…”

Section: Introductionmentioning

confidence: 99%

DNA Origami‐Enabled Engineering of Ligand–Drug Conjugates for Targeted Drug Delivery

Guo

et al. 2020

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under the context that Brentuximab vedotin (Adcetris) for relapsed Hodgkin lymphoma [5,6] and T-DM1 (Kadcyla) for HER2 + metastatic breast cancer [7,8] received clinical approval from the Food and Drug Administration (FDA). The socalled "magic bullet," originally conceived by Paul Ehrlich, [9] are designed to combine the toxicity of small-molecule drugs with the targeting ability of antibodies to improve overall efficacy and therapeutic index. [10][11][12][13][14][15] Although conceptually straightforward, development of ADCs is encountered with several challenges including manageable toxicity, homogeneous conjugation and limited drug payload capacity. The balance between drug-to-antibody ratio (DAR) and targeting capability is mandatory for ADCs to reduce the attrition rate of drug candidates. Very high DAR ADCs may suffer decreased recognition to the target antigen. [16][17][18][19] Hence, it is highly desirable to develop ADCs with both high maximum tolerated doses and high selectivity. [20][21][22] Recently, the bloom of structural DNA nanotechnology [23,24] has demonstrated unprecedented precision on structural control, which enables predictable and programmable construction of complex nanostructures by exploiting intra-and inter-molecular Watson-Crick base-pairing. The programmability and addressability of DNA origami nanostructures (DONs) enable multiple desired functional moieties (such as therapeutic cargoes and tumor targeting ligands) with designer geometry and density. [25][26][27] Therefore, DONs have been increasingly employed for developing novel drug delivery systems [28,29] due to their versatile designability, high solubility, and intrinsic biocompatibility. [30][31][32][33][34][35][36][37] Moreover, certain types of DONs have been proven to be readily rapidly internalized by mammalian cells despite their negatively charged surface property. [38] We herein propose that DONs with certain framework [39] could serve as an ideal scaffold for ADCs analogues with exceptional control over targeting ligand density and drug loading contents for optimized antitumor efficacies and safety profile. [40] Specifically, we construct a new prostate cancer (PCa)specific drug delivery system by introducing different numbers of ligand 2-[3-(1,3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) to a designed six-helical-bundle DNA origami nanostructure (6HB DON). DUPA has been demonstrated to be a high-affinity inhibitor (K i ≈ 0.02 × 10 −9 -0.1 × 10 −9 m) for prostate-specific membrane antigen (PSMA). [41] We incorporate this Effective drug delivery systems that can systematically and selectively transport payloads to disease cells remain a challenge. Here, a targeting ligandmodified DNA origami nanostructure (DON) as an antibody-drug conjugate (ADC)-like carrier for targeted prostate cancer therapy is reported. Specifically, DON of six helical bundles is modified with a ligand 2-[3-(1,3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) against prostate-specific membrane antigen (PSMA), to serve as the antibody f...

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“…Interestingly, the associated siRNA can only be displaced by total cellular RNA and cell lysis (Figure b, bottom panel). This dissociation triggered by the presence of long dsRNA (in the secondary structure of mRNA) is remarkable because 1) it demonstrates the substrate specificity for dsRBD and 2) it provides a unique mechanism for siRNA release (cargo unpackaging) once inside the cytoplasm …”

Section: Resultsmentioning

confidence: 99%

“…Inspired by nature, we have previously demonstrated the assembly of an RNP octamer nanoparticle for immobilization of siRNA and siRNA‐aptamer chimeras . The nanoparticle complex not only is stable in blood circulation but also offers significantly improved binding affinity to target cells due to the multivalency effect.…”

Section: Introductionmentioning

confidence: 99%

Ribonucleoprotein: A Biomimetic Platform for Targeted siRNA Delivery

Tai

Gao

2019

Adv Funct Materials

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Many small interfering RNA (siRNA) carriers have been developed over the years, mostly based on cationic lipids and polymers that can condense siRNA into nanoparticle complexes and aid in endosomal escape. In comparison, development of charge-neutral siRNA carriers to avoid or reduce nonspecific binding, aggregation, and toxicity is limited, due to a lack of mechanisms for carrier-siRNA association beyond electrostatic interaction. Here, a unique, charge-neutral, biomimetic platform is reported, mimicking the natural state of functional RNA, ribonucleoprotein (RNP). This RNP architecture is simple to make, precise in assembly stoichiometry, stable in serum, and biocompatible. Gene knockdown is achieved in vitro and in vivo, demonstrating excellent potential for translation.

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A ribonucleoprotein octamer for targeted siRNA delivery

Cited by 69 publications

References 54 publications

Development of “CLAN” Nanomedicine for Nucleic Acid Therapeutics

Development of “CLAN” Nanomedicine for Nucleic Acid Therapeutics

DNA Origami‐Enabled Engineering of Ligand–Drug Conjugates for Targeted Drug Delivery

Ribonucleoprotein: A Biomimetic Platform for Targeted siRNA Delivery

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