Lipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy

Zong, Yi; Lin, Yi; Wei, Tuo; Cheng, Qiang

doi:10.1002/adma.202303261

Cited by 70 publications

(50 citation statements)

References 216 publications

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“…Additionally, LNPs-miRNA-193b exhibited significant delays in leukemia propagation in acute myeloid leukemia xenograft models, while LNPs containing miR-182 impaired tumor growth in triple-negative breast cancer models. , Optimal LNPs should maximize the probability of reaching specific cell types within a target organ and minimize the toxicity and immunogenicity of cargoes . To enhance the stability, transfection efficacy, and safety of LNPs, various optimization strategies such as component selection, surface modification, suitable administration routes, and design of bioinspired compositions and structures have been explored . However, regarding the oral delivery of LNPs, more efforts are required to overcome the challenges presented by the complex digestive tract environment .…”

Section: Resultsmentioning

confidence: 99%

“…43 To enhance the stability, transfection efficacy, and safety of LNPs, various optimization strategies such as component selection, surface modification, suitable administration routes, and design of bioinspired compositions and structures have been explored. 44 However, regarding the oral delivery of LNPs, more efforts are required to overcome the challenges presented by the complex digestive tract environment. 45 Nonetheless, the restoration of the miR-200 family through a LNPs-based delivery system holds great promise for improving therapeutic efficacy in patients with enteritis or active UC.…”

Section: Delivery Of Mir-200 Via Lipid Nanoparticles Facilitates Inte...mentioning

confidence: 99%

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MicroRNA-200 Loaded Lipid Nanoparticles Promote Intestinal Epithelium Regeneration in Canonical MicroRNA-Deficient Mice

Wei,

Yu,

Zhang

et al. 2023

ACS Nano

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Intestinal epithelium undergoes regeneration after injuries, and the disruption of this process can lead to inflammatory bowel disease and tumorigenesis. Intestinal stem cells (ISCs) residing in the crypts are crucial for maintaining the intestinal epithelium's homeostasis and promoting regeneration upon injury. However, the precise role of DGCR8, a critical component in microRNA (miRNA) biogenesis, in intestinal regeneration remains poorly understood. In this study, we provide compelling evidence demonstrating the indispensable role of epithelial miRNAs in the regeneration of the intestine in mice subjected to 5-FU or irradiation-induced injury. Through a comprehensive pooled screen of miRNA function in Dgcr8-deficient organoids, we observe that the loss of the miR-200 family leads to the hyperactivation of the p53 pathway, thereby reducing ISCs and impairing epithelial regeneration. Notably, downregulation of the miR-200 family and hyperactivation of the p53 pathway are verified in colonic tissues from patients with active ulcerative colitis (UC). Most importantly, the transient supply of miR-200 through the oral delivery of lipid nanoparticles (LNPs) carrying miR-200 restores ISCs and promotes intestinal regeneration in mice following acute injury. Our study implies the miR-200/p53 pathway as a promising therapeutic target for active UC patients with diminished levels of the miR-200 family. Furthermore, our findings suggest that the clinical application of LNP-miRNAs could enhance the efficacy, safety, and acceptability of existing therapeutic modalities for intestinal diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Delivery Of Mir-200 Via Lipid Nanoparticles Facilitates Inte...mentioning

confidence: 99%

MicroRNA-200 Loaded Lipid Nanoparticles Promote Intestinal Epithelium Regeneration in Canonical MicroRNA-Deficient Mice

Wei,

Yu,

Zhang

et al. 2023

ACS Nano

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“…The delivery of mRNA is notoriously difficult through simple binding using traditional gene vectors because of the conformation of linear and irregularly elongated mRNA molecules; therefore, efforts have been made to develop ideal mRNA delivery carriers to achieve satisfactory delivery efficiency. 39,40 Indeed, Mai et al reported the use of protamine to concentrate mRNA and encapsulation by DOTAP/Chol/DSPE-PEG cationic liposomes, whereby the cationic liposome/protamine complex exhibited highly effi- 43 Although significant progress has been made in this field, limitations still exist in many aspects, including poor transfection efficiency or the use of "multivector systems" that increase the complexity of mRNA delivery vectors, leading to uncertainty regarding the prepared mRNA formulations. In our study, we demonstrated that the MLSV system can deliver mRNA with high efficiency.…”

Section: ■ Discussionmentioning

confidence: 99%

“…The high efficiency of mRNA delivery is the key point of mRNA-based tumor gene therapy. The delivery of mRNA is notoriously difficult through simple binding using traditional gene vectors because of the conformation of linear and irregularly elongated mRNA molecules; therefore, efforts have been made to develop ideal mRNA delivery carriers to achieve satisfactory delivery efficiency. , Indeed, Mai et al reported the use of protamine to concentrate mRNA and encapsulation by DOTAP/Chol/DSPE-PEG cationic liposomes, whereby the cationic liposome/protamine complex exhibited highly efficient mRNA delivery . Capasso Palmiero et al reported the synthesis of PBAE terpolymers-based diacrylates and dodecyl amine to deliver mRNA with spleen accumulation .…”

Section: Discussionmentioning

confidence: 99%

Tumor Cell Lysate-Based Multifunctional Nanoparticles Facilitate Enhanced mRNA Delivery and Immune Stimulation for Melanoma Gene Therapy

Huang,

Wang,

et al. 2023

Mol. Pharmaceutics

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Messenger ribonucleic acid (mRNA)-based gene therapy has great potential for cancer gene therapy. However, the effectiveness of mRNA in cancer therapy needs to be further improved, and the delivery efficiency and instability of mRNA limit the application of mRNA-based products. Both the delivery efficiency can be elevated by cell-penetrating peptide modification, and the immune response can be enhanced by tumor cell lysate stimulation, representing an advantageous strategy to expand the effectiveness of mRNA gene therapy. Therefore, it is vital to exploit a vector that can deliver high-efficiency mRNA with codelivery of tumor cell lysate to induce specific immune responses. We previously reported that DMP cationic nanoparticles, formed by the self-assembly of DOTAP and mPEG-PCL, can deliver different types of nucleic acids. DMP has been successfully applied in gene therapy research for various tumor types. Here, we encapsulated tumor cell lysates with DMP nanoparticles and then modified them with a fused cell-penetrating peptide (TAT-iRGD) to form an MLSV system. The MLSV system was loaded with encoded Bim mRNA, forming the MLSV/Bim complex. The average size of the synthesized MLSV was 191.4 nm, with a potential of 47.8 mV. The MLSV/mRNA complex promotes mRNA absorption through caveolin-mediated endocytosis, with a transfection rate of up to 68.6% in B16 cells. The MLSV system could also induce the maturation and activation of dendritic cells, obviously promoting the expression of CD80, CD86, and MHC-II both in vitro and in vivo. By loading the encoding Bim mRNA, the MLSV/Bim complex can inhibit cell proliferation and tumor growth, with inhibition rates of up to 87.3% in vitro. Similarly, the MLSV/Bim complex can inhibit tumor growth in vivo, with inhibition rates of up to 78.7% in the B16 subcutaneous tumor model and 63.3% in the B16 pulmonary metastatic tumor model. Our results suggest that the MLSV system is an advanced candidate for mRNA-based immunogene therapy.

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“…[3] mRNA is an unstable single-stranded macromolecule with a negative charge, a suitable carrier vehicle is crucial for ensuring enhanced target delivery in vivo. [4] The greenlighted mRNA vaccines against COVID-19 which deliver mRNA based on LNP (ALC-0315 LNP or SM102 LNP), Onpattro, is approved by the FDA for the therapy of hereditary transthyretin (TTR)-mediated amyloidosis which is based on DLin-MC3-DMA (MC3) lipid; literature reports have proved that MC3-based LNP can effectively deliver mRNA in vivo. [1,5] However, the mRNA-LNP vaccine has been limited by the safety of administration by repeated or high doses.…”

Section: Introductionmentioning

confidence: 99%

Delivery of mRNA Vaccine with 1, 2‐Diesters‐Derived Lipids Elicits Fast Liver Clearance for Safe and Effective Cancer Immunotherapy

Xu,

Hu,

Xia

et al. 2023

Adv Healthcare Materials

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Messenger RNA (mRNA) vaccine is explored as a promising strategy for cancer immunotherapy, but the side effects, especially the liver‐related damage caused by LNP, raise concerns about its safety. In this study, a novel library of 248 ionizable lipids comprising 1,2‐diesters is designed via a two‐step process involving the epoxide ring‐opening reaction with carboxyl group‐containing alkyl chains followed by an esterification reaction with the tertiary amines. Owing to the special chemical structure of 1,2‐diesters, the top‐performing lipids and formulations exhibit a faster clearance rate in the liver, contributing to increased stability and higher safety compared with DLin‐MC3‐DMA. Moreover, the LNP shows superior intramuscular mRNA delivery and elicits robust antigen‐specific immune activation. The vaccinations delivered by the LNP system suppress tumor growth and prolong survival in both model human papillomavirus E7 and ovalbumin antigen‐expressing tumor models. Finally, the structure of lipids which enhances the protein expression in the spleen and draining lymph nodes compared with ALC‐0315 lipid in Comirnaty is further optimized. In conclusion, the 1, 2‐diester‐derived lipids exhibit rapid liver clearance and effective anticancer efficiency to different types of antigens‐expressing tumor models, which may be a safe and universal platform for mRNA vaccines.

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Lipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy

Cited by 70 publications

References 216 publications

MicroRNA-200 Loaded Lipid Nanoparticles Promote Intestinal Epithelium Regeneration in Canonical MicroRNA-Deficient Mice

MicroRNA-200 Loaded Lipid Nanoparticles Promote Intestinal Epithelium Regeneration in Canonical MicroRNA-Deficient Mice

Tumor Cell Lysate-Based Multifunctional Nanoparticles Facilitate Enhanced mRNA Delivery and Immune Stimulation for Melanoma Gene Therapy

Delivery of mRNA Vaccine with 1, 2‐Diesters‐Derived Lipids Elicits Fast Liver Clearance for Safe and Effective Cancer Immunotherapy

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