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羟氯喹啉衍生的可电离脂质促进脾靶向转染并增强癌症免疫治疗。

Hydroxychloroquine-Derived Ionizable Lipid Facilitates Spleen-Tropic Transfection and Enhances Cancer Immunotherapy.

作者信息

Fan Jiaqi, Wei Qi, Yuan Pengcheng, Xiao Bing, Yao Shasha, Xu Haoran, Liu Jiwei, Li Ruoshui, Shen Youqing, Slater Nigel K H, Tang Jianbin

机构信息

Zhejiang Key Laboratory of Smart Biomaterials, Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China.

出版信息

Chem Bio Eng. 2025 Jun 18;2(7):437-448. doi: 10.1021/cbe.5c00031. eCollection 2025 Jul 24.

DOI:10.1021/cbe.5c00031
PMID:40735013
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12301932/
Abstract

The success of SARS-CoV-2 mRNA vaccines has boosted their development against various diseases, especially tumors. However, their clinical application is hindered by limited therapeutic efficacy and non-negligible side effects. Many studies attempt to improve therapeutic effect against tumors by using spleen-tropism mRNA delivery systems. Herein, we develop lipid nanoparticles (LNPs) based on hydroxychloroquine (HCQ)-derived ionizable lipid as a spleen-tropism mRNA delivery system that simultaneously modulates the tumor immune-suppressive microenvironment. The screened HCQ LNPs exhibit high mRNA transfection efficiency both and . Surprisingly, the HCQ LNP can achieve spleen-tropic transfection after systemic administration, which is conducive to immune cells for antigen presentation. In addition, HCQ LNP passively targeted to tumors significantly repolarizes tumor-associated macrophages to the M1 phenotype, thereby modulating the tumor microenvironment. Therefore, compared to the commercial MC-3 LNP/mOVA, HCQ LNP/mOVA shows significantly improved prophylactic and therapeutic antitumor efficacy and antimetastatic effect. HCQ LNP/mOVA demonstrates a multifaceted strategy that enhances the therapeutic efficacy of mRNA tumor vaccines through functional mRNA delivery system design.

摘要

严重急性呼吸综合征冠状病毒2（SARS-CoV-2）信使核糖核酸（mRNA）疫苗的成功推动了其针对各种疾病，尤其是肿瘤的研发。然而，其临床应用受到治疗效果有限和不可忽视的副作用的阻碍。许多研究试图通过使用脾靶向mRNA递送系统来提高对肿瘤的治疗效果。在此，我们开发了基于羟氯喹（HCQ）衍生的可电离脂质的脂质纳米颗粒（LNPs）作为脾靶向mRNA递送系统，该系统同时调节肿瘤免疫抑制微环境。筛选出的HCQ LNPs在体外和体内均表现出高mRNA转染效率。令人惊讶的是，HCQ LNP在全身给药后可实现脾靶向转染，这有利于免疫细胞进行抗原呈递。此外，被动靶向肿瘤的HCQ LNP可使肿瘤相关巨噬细胞显著重极化至M1表型，从而调节肿瘤微环境。因此，与商业化的MC-3 LNP/mOVA相比，HCQ LNP/mOVA显示出显著提高的预防和治疗抗肿瘤疗效以及抗转移作用。HCQ LNP/mOVA展示了一种多方面的策略，即通过功能性mRNA递送系统设计来提高mRNA肿瘤疫苗的治疗效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/dfb965f3a47d/be5c00031_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/856a25b1a080/be5c00031_0008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/66855cae1816/be5c00031_0003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/dfb965f3a47d/be5c00031_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/856a25b1a080/be5c00031_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/ea075309cca7/be5c00031_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/3d1b3c36c2ca/be5c00031_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/66855cae1816/be5c00031_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/6ba4d08d139c/be5c00031_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/e82243dd50dd/be5c00031_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/d56a33665595/be5c00031_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a617/12301932/dfb965f3a47d/be5c00031_0007.jpg

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本文引用的文献

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Engineered Extracellular Vesicles as a New Class of Nanomedicine.工程化细胞外囊泡作为一类新型纳米药物。
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Glycopolypeptide Coordinated Nanovaccine: Fabrication, Characterization, and Antitumor Immune Response.糖多肽配位纳米疫苗：制备、表征及抗肿瘤免疫反应
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Organ- and Cell-Selective Delivery of mRNA In Vivo Using Guanidinylated Serinol Charge-Altering Releasable Transporters.利用胍基化丝氨醇电荷修饰可释放转运体在体实现器官和细胞选择性 mRNA 递送。
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In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors.用于 mRNA 治疗药物和基因编辑系统递释的可降解分支型脂质体的原位组合合成。
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