Exosomes as targeted delivery platform of CRISPR/Cas9 for therapeutic genome editing

Loss-of-function mutations in Angiopoietin-like 3 (Angptl3) are associated with lowered blood lipid levels, making Angptl3 an attractive therapeutic target for the treatment of human lipoprotein metabolism disorders. In this study, we developed a lipid nanoparticle delivery platform carrying Cas9 messenger RNA (mRNA) and guide RNA for CRISPR-Cas9–based genome editing of Angptl3 in vivo. This system mediated specific and efficient Angptl3 gene knockdown in the liver of wild-type C57BL/6 mice, resulting in profound reductions in serum ANGPTL3 protein, low density lipoprotein cholesterol, and triglyceride levels. Our delivery platform is significantly more efficient than the FDA-approved MC-3 LNP, the current gold standard. No evidence of off-target mutagenesis was detected at any of the nine top-predicted sites, and no evidence of toxicity was detected in the liver. Importantly, the therapeutic effect of genome editing was stable for at least 100 d after a single dose administration. This study highlights the potential of LNP-mediated delivery as a specific, effective, and safe platform for Cas9-based therapeutics.

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Mitochondrion-specific dendritic lipopeptide liposomes for targeted sub-cellular delivery

Nature Communications ◽

10.1038/s41467-021-22594-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lei Jiang ◽

Sensen Zhou ◽

Xiaoke Zhang ◽

Cheng Li ◽

Shilu Ji ◽

...

Keyword(s):

Targeted Delivery ◽

Cellular Delivery ◽

Cell Penetration ◽

Photodynamic Treatment ◽

Cellular Compartment ◽

Peptide Moiety ◽

Delivery Platform ◽

Liposomal Delivery ◽

Tumor Accumulation ◽

Complete Tumor

AbstractThe mitochondrion is an important sub-cellular organelle responsible for the cellular energetic source and processes. Owing to its unique sensitivity to heat and reactive oxygen species, the mitochondrion is an appropriate target for photothermal and photodynamic treatment for cancer. However, targeted delivery of therapeutics to mitochondria remains a great challenge due to their location in the sub-cellular compartment and complexity of the intracellular environment. Herein, we report a class of the mitochondrion-targeted liposomal delivery platform consisting of a guanidinium-based dendritic peptide moiety mimicking mitochondrion protein transmembrane signaling to exert mitochondrion-targeted delivery with pH sensitive and charge-reversible functions to enhance tumor accumulation and cell penetration. Compared to the current triphenylphosphonium (TPP)-based mitochondrion targeting system, this dendritic lipopeptide (DLP) liposomal delivery platform exhibits about 3.7-fold higher mitochondrion-targeted delivery efficacy. Complete tumor eradication is demonstrated in mice bearing 4T1 mammary tumors after combined photothermal and photodynamic therapies delivered by the reported DLP platform.

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Scaffold-mediated non-viral delivery platform for CRISPR/Cas9-based genome editing

Acta Biomaterialia ◽

10.1016/j.actbio.2019.04.020 ◽

2019 ◽

Vol 90 ◽

pp. 60-70 ◽

Cited By ~ 9

Author(s):

Jiah Shin Chin ◽

Wai Hon Chooi ◽

Hongxia Wang ◽

William Ong ◽

Kam W. Leong ◽

...

Keyword(s):

Genome Editing ◽

Delivery Platform

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Enhanced combination cancer therapy using lipid-calcium carbonate/phosphate nanoparticles as a targeted delivery platform

Nanomedicine ◽

10.2217/nnm-2018-0252 ◽

2019 ◽

Vol 14 (1) ◽

pp. 77-92 ◽

Cited By ~ 5

Author(s):

Yilun Wu ◽

Wenyi Gu ◽

Zhi Ping Xu

Keyword(s):

Calcium Carbonate ◽

Cancer Therapy ◽

Targeted Delivery ◽

Combination Cancer Therapy ◽

Delivery Platform

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Carbon Nanotubes as A High-Performance Platform for Target Delivery of Anticancer Quinones

Current Pharmaceutical Design ◽

10.2174/1381612825666190117095132 ◽

2019 ◽

Vol 24 (43) ◽

pp. 5207-5218 ◽

Cited By ~ 1

Author(s):

H.V. Grushevskaya ◽

N.G. Krylova

Keyword(s):

Carbon Nanotubes ◽

Targeted Delivery ◽

High Performance ◽

Biological Fluid ◽

Specific Interaction ◽

Antitumor Drugs ◽

Anthracycline Antibiotics ◽

Delivery Platform ◽

Characteristic Features ◽

Tumor Microenviroment

Background: In spite of considerable efforts of researchers the cancer deseases remain to be incurable and a percentage of cancer deseases in the structure of mortality increases every year. At that, high systemic toxicity of antitumor drugs hampers their effective use. Because of this fact, the development of nanosystems for targeted delivery of antitumor drugs is one of the leading problem in nanomedicine and nanopharmacy. Objective: To critically examine the modern strategies for carbon nanotubes (CNTs)-based delivery of anticancer quinones and to summarize the mechanisms which can provide high effectiveness and multifunctionality of the CNT-based quinone delivery platform. Results: Quinones, including anthracycline antibiotics – doxorubicin and daunorubicin, are among the most prospective group of natural and syntetic compounds which exhibit high antitumor activity against different type of tumors. In this review, we focus on the possibilities of using CNTs for targeted delivery of antitumor compounds with quinoid moiety which is ordinarily characterized by high specific interaction with DNA molecules. Quinones can be non-covalently adsorbed on CNT surface due to their aromatic structure and π-conjugated system of double bonds. The characteristic features of doxorubicine-CNT complex are high loading efficiency, pH-dependent release in acidic tumor microenviroment, enough stability in biological fluid. Different types of CNT functionalization, targeting strategies and designs for multifunctional CNT-based doxorubicine delivery platform are disscussed. Conclusion: Nanosystems based on functionalized CNTs are very promising platform for quinone delivery resulting in significant enhancement of cancer treatment efficiency. Functionalization of CNTs with the polymeric shell, especially DNA-based shells, can provide the greatest affinity and mimicry with biological structures.

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Monocyte-derived multipotent cell delivered programmed therapeutics to reverse idiopathic pulmonary fibrosis

Science Advances ◽

10.1126/sciadv.aba3167 ◽

2020 ◽

Vol 6 (22) ◽

pp. eaba3167 ◽

Cited By ~ 1

Author(s):

Xin Chang ◽

Lei Xing ◽

Yi Wang ◽

Chen-Xi Yang ◽

Yu-Jing He ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Targeted Delivery ◽

Alveolar Epithelial Cell ◽

Synergetic Effect ◽

Engineered Nanoparticles ◽

Matrix Metalloproteinase 2 ◽

Alveolar Epithelial ◽

The Matrix ◽

Delivery Platform

Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous and fatal disease. However, IPF treatment has been limited by the low drug delivery efficiency to lungs and dysfunctional “injured” type II alveolar epithelial cell (AEC II). Here, we present surface-engineered nanoparticles (PER NPs) loading astaxanthin (AST) and trametinib (TRA) adhered to monocyte-derived multipotent cell (MOMC) forming programmed therapeutics (MOMC/PER). Specifically, the cell surface is designed to backpack plenty of PER NPs that reach directly to the lungs due to the homing characteristic of the MOMC and released PER NPs retarget injured AEC II after responding to the matrix metalloproteinase-2 (MMP-2) in IPF tissues. Then, released AST can enhance synergetic effect of TRA for inhibiting myofibroblast activation, and MOMC can also repair injured AEC II to promote damaged lung regeneration. Our findings provide proof of concept for developing a strategy for cell-mediated lung-targeted delivery platform carrying dual combined therapies to reverse IPF.

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Development of a Novel Oral Delivery Vehicle for Probiotics

Current Pharmaceutical Design ◽

10.2174/1381612826666200210111925 ◽

2020 ◽

Vol 26 (26) ◽

pp. 3134-3140 ◽

Cited By ~ 1

Author(s):

Kevin Enck ◽

Surya Banks ◽

Hariom Yadav ◽

Mark E. Welker ◽

Emmanuel C. Opara

Keyword(s):

Targeted Delivery ◽

Oral Delivery ◽

Oral Drug Delivery ◽

Oral Drug ◽

Bacterial Cells ◽

Alginate Hydrogel ◽

Chemically Modified ◽

Delivery Platform ◽

Ph Conditions

Background: There is a significant interest in effective oral drug delivery of therapeutic substances. For probiotics, there is a particular need for a delivery platform that protects the bacteria from destruction by the acidic stomach while enabling targeted delivery to the intestine where microbiota naturally reside. The use of probiotics and how they impact the gut microbiota is a growing field and holds promise for the treatment of a variety of gastrointestinal diseases, including irritable bowel disease Crohn’s disease and C. diff and other diseases, such as obesity, diabetes, Parkinson’s, and Alzheimer’s diseases. Objective: The aim of this research was to use our newly developed chemically-modified alginate hydrogel with the characteristic feature of stability in acidic environments but disintegration under neutral-basic pH conditions to design a novel system for effective targeted delivery of ingested probiotics. Method and Results: We have used the approach of encapsulation of bacterial cells in the hydrogel of the modified alginate with in vitro studies in both simulated stomach acid and intestinal fluid conditions to demonstrate the potential application of this novel platform in oral delivery of probiotics. Our data provide a proof-of-concept that enables further studies in vivo with this delivery platform. Conclusion: We have demonstrated in the present study that our chemically modified alginate hydrogel is resistant to acidic conditions and protects bacterial cells encapsulated in it, but it is sensitive to neutral-basic pH conditions under which it disintegrates and releases its viable bacteria cell payload. Our data provide a proof-ofconcept that enables further studies in vivo with this delivery platform for the efficacy of therapeutic bacteria in various disease conditions.

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