Shear-responsive peptide/siRNA complexes as lung-targeting gene vectors

Yin, Dali; Zhang, Mengjie; Chen, Jiaxin; Huang, Yuanyu; Liang, Dehai

doi:10.1016/j.cclet.2020.12.005

Cited by 18 publications

(8 citation statements)

References 55 publications

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“…, virus protein facilitated membrane fusion and electric field mediated electroporation), to facilitate early endosomal escape of siRNA and thereby increase the efficacy of siRNA-mediated gene silencing. Consequently, various delivery carriers, such as lipid nanoparticles, − polymers, ,− inorganic nanoparticles, − peptides, − extracellular vesicles, ,− and siRNA-conjugates − have been developed to transport siRNA effectively and specifically to the intended site in a gretaer amount.…”

Section: Introductionmentioning

confidence: 99%

Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA

Zhou

et al. 2021

Nano Lett.

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Efficient endosomal escape is the most essential but challenging issue for siRNA drug development. Herein, a series of quaternary ammonium-based amphiphilic triblock polymers harnessing an elaborately tailored pH-sensitive hydrophobic core were synthesized and screened. Upon incubating in an endosomal pH environment (pH 6.5–6.8), mPEG45-P(DPA50-co-DMAEMA56)-PT53 (PDDT, the optimized polymer) nanomicelles (PDDT-Ms) and PDDT-Ms/siRNA polyplexes rapidly disassembled, leading to promoted cytosolic release of internalized siRNA and enhanced silencing activity evident from comprehensive analysis of the colocalization and gene silencing using a lysosomotropic agent (chloroquine) and an endosomal trafficking inhibitor (bafilomycin A1). In addition, PDDT-Ms/siPLK1 dramatically repressed tumor growth in both HepG2-xenograft and highly malignant patient-derived xenograft models. PDDT-Ms-armed siPD-L1 efficiently blocked the interaction of PD-L1 and PD-1 and restored immunological surveillance in CT-26-xenograft murine model. PDDT-Ms/siRNA exhibited ideal safety profiles in these assays. This study provides guidelines for rational design and optimization of block polymers for efficient endosomal escape of internalized siRNA and cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA

Zhou

et al. 2021

Nano Lett.

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“…First, the targeting ligands increase the complexity of delivery system, hindering the rapid production of the mRNA vaccine. Second, as it is challenging to transfect immune cells in vivo, the successful mRNA delivery and transfection to lymphoid organs are still rarely reported ( 20 , 21 ).…”

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confidence: 99%

Lipid nanoparticle-mediated lymph node–targeting delivery of mRNA cancer vaccine elicits robust CD8 ⁺ T cell response

Chen

Huang

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

158

135

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The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted delivery to the lymph node (LN) is predicted to reduce side effects and increase the immune response. In this study, we explored an endogenously LN-targeting lipid nanoparticle (LNP) without the modification of any active targeting ligands for developing an mRNA cancer vaccine. The LNP named 113-O12B showed increased and specific expression in the LN compared with LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. The targeted delivery of mRNA to the LN increased the CD8 + T cell response to the encoded full-length ovalbumin (OVA) model antigen. As a result, the protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen–bearing B16F10 melanoma model was also improved. Moreover, 113-O12B encapsulated with TRP-2 peptide (TRP2 180–188 )–encoding mRNA also exhibited excellent tumor inhibition, with the complete response of 40% in the regular B16F10 tumor model when combined with anti–programmed death-1 (PD-1) therapy, revealing broad application of 113-O12B from protein to peptide antigens. All the treated mice showed long-term immune memory, hindering the occurrence of tumor metastatic nodules in the lung in the rechallenging experiments that followed. The enhanced antitumor efficacy of the LN-targeting LNP system shows great potential as a universal platform for the next generation of mRNA vaccines.

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“…Peptides are other possible carriers that can be applied for siRNA delivery because of their stability, low cytotoxicity and immunogenicity, biocompatibility, and biodegradabity 179 , 180 . Peptides can be used alone or as an assistant component to other systems, such as fusogenic peptides used to bypass the endosomal entrapment barrier and cell-penetrating peptides (CPPs) used to facilitate the cellular entry 181 .…”

Section: Sirna Delivery Systems For Treatment Of Ali/ardsmentioning

confidence: 99%

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

Zoulikha

Xiao

Boafo

et al. 2022

Acta Pharmaceutica Sinica B

139

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The use of small interfering RNAs (siRNAs) has been under investigation for the treatment of several unmet medical needs, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS) wherein siRNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the mRNA level. The clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy. However, the clinical translation of siRNA is hampered by the inefficient delivery of siRNA therapeutics to the target cells due to the properties of naked siRNA. Thus, this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable siRNA formulations for human use before siRNA therapeutics for ALI/ARDS become available in the clinic.

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Shear-responsive peptide/siRNA complexes as lung-targeting gene vectors

Cited by 18 publications

References 55 publications

Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA

Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA

Lipid nanoparticle-mediated lymph node–targeting delivery of mRNA cancer vaccine elicits robust CD8 ⁺ T cell response

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

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Shear-responsive peptide/siRNA complexes as lung-targeting gene vectors

Cited by 18 publications

References 55 publications

Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA

Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA

Lipid nanoparticle-mediated lymph node–targeting delivery of mRNA cancer vaccine elicits robust CD8 + T cell response

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

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Product

Resources

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Lipid nanoparticle-mediated lymph node–targeting delivery of mRNA cancer vaccine elicits robust CD8 ⁺ T cell response