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Branched hydrophobic tails in lipid nanoparticles enhance mRNA delivery for cancer immunotherapy.
Yan, Yunfeng; Liu, Xiaomin; Wang, Longyu; Wu, Chengfan; Shuai, Qi; Zhang, Yanmei; Liu, Shuai.
Afiliación
  • Yan Y; College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: yfyan@zjut.edu.cn.
  • Liu X; College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China.
  • Wang L; College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China.
  • Wu C; College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China.
  • Shuai Q; Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, China.
  • Zhang Y; School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, 310013, China.
  • Liu S; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Biomaterials ; 301: 122279, 2023 10.
Article en En | MEDLINE | ID: mdl-37591187
Efficient and safe delivery of vulnerable mRNA is a long-standing challenge for the broad application of the emerging mRNA-based therapeutics. Herein, a combinatorial library containing 119 novel lipids was constructed via sequential aza-Michael addition reactions of arylates and varying amines to tackle the ongoing challenge in mRNA delivery. Through in vitro screening of the lipid library on IGROV 1 cells, we identified several synthetic lipids with superior mRNA delivery efficacy. The delivery capability of these lipids was verified by the potent expression of luciferase in BALB/c mice upon intravenous administration of luciferase-encoding mRNA lipid nanoparticles (LNPs). Further investigations on the structure-activity relationship revealed that lipids with branched hydrophobic tails were better at delivering mRNA than those containing linear tails at the similar total number of carbons. In comparison to linear tails, the branched tails endowed LNPs with less inner hydrophobicity, fewer surface charges, and proper stability, which benefits the cellular uptake of LNPs and the intracellular trafficking of mRNA, thus improves the delivery efficacy of mRNA. The therapeutical potential of the lead LNPs was evaluated by delivering ovalbumin (OVA)-encoding mRNA to mice bearing B16-OVA melanoma tumors. The results demonstrated that the administration of OVA mRNA LNPs significantly activated CD8+ T cells in tumor microenvironment and substantially prohibited the growth of the aggressive B16-OVA tumors. The robust antitumor efficacy highlights the great potential of these LNPs in cancer immunotherapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Melanoma Experimental / Linfocitos T CD8-positivos Límite: Animals Idioma: En Revista: Biomaterials Año: 2023 Tipo del documento: Article Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Melanoma Experimental / Linfocitos T CD8-positivos Límite: Animals Idioma: En Revista: Biomaterials Año: 2023 Tipo del documento: Article Pais de publicación: Países Bajos