A naturally derived lipopeptide lipid nanoparticle platform enabling multiple nucleic acids delivery

IF 18 1区医学 Q1 ENGINEERING, BIOMEDICAL

Bioactive Materials Pub Date : 2025-09-11 DOI:10.1016/j.bioactmat.2025.09.007

Han Xiao , Bailing Feng , Dongdong Gao , Shuangni Shi , Yiqing Yang , Yiwei Zhang , Fengyang Wang , Qi Yao , Haiqing Song , Ying Liu , Gang Cheng

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引用次数: 0

Abstract

Lipid nanoparticles (LNPs) have emerged as versatile platforms for nucleic acid-based therapies. Despite advancements, key challenges remain in achieving tissue-specific delivery while maintaining low toxicity and tunable properties essential for therapeutic applications. Here, we report a novel high-performance LNP platform employing arginine-histidine peptide-dioleoylphosphatidylethanolamine (RmHnC-DOPE) lipopeptides as core components. Through systematic optimization of arginine-to-histidine ratios, we engineered three variants, R3H7C-DOPE, R4H6C-DOPE, and R5H5C-DOPE, enabling payload-specific and tissue-selective delivery of siRNA, mRNA, and plasmid DNA. In vitro evaluation demonstrated superior gene silencing efficiency for R4H6C-DOPE (85.1%) and R5H5C-DOPE (89.5%) compared to benchmark SM-102 LNPs (67.4%), while maintaining >99% cell viability. R5H5C-DOPE exhibited exceptional broad-spectrum delivery, achieving 74.8% and 92.1% transfection efficiency for mRNA and pDNA, respectively. Notably, R3H7C-DOPE showed 11-fold enhanced pDNA expression relative to SM-102. In vivo studies revealed R3H7C-DOPE's superior hepatic targeting, achieving >2-fold greater PCSK9 suppression (14.1 ± 7.3% residual expression at day 28) versus SM-102 (53.8 ± 41.2% at day 7). R5H5C-DOPE demonstrated remarkable extrahepatic targeting with >90% pulmonary localization, effectively overcoming the hepatic tropism of conventional LNPs. Comprehensive safety assessments revealed exceptional biocompatibility of RmHnC-DOPE formulations, with 100% survival rates across mouse strains, contrasting sharply with SM-102-induced severe toxicity and mortality. Long-term studies confirmed sustained tolerability with preserved organ function and minimal inflammatory responses. This versatile platform combines superior biocompatibility, precise tissue targeting, and synthetic accessibility, providing a clinically viable solution for diverse gene delivery applications spanning hepatic silencing and extrahepatic therapeutics.

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天然衍生的脂肽脂质纳米颗粒平台，使多种核酸递送

脂质纳米颗粒（LNPs）已成为基于核酸的治疗的多功能平台。尽管取得了进步，但在实现组织特异性递送的同时保持治疗应用所需的低毒性和可调特性仍然存在关键挑战。在这里，我们报告了一个新的高性能LNP平台，以精氨酸-组氨酸肽-二油基磷脂酰乙醇胺（RmHnC-DOPE）脂肽为核心成分。通过系统优化精氨酸与组氨酸的比例，我们设计了三种变体，R3H7C-DOPE、R4H6C-DOPE和R5H5C-DOPE，实现了siRNA、mRNA和质粒DNA的有效载荷特异性和组织选择性传递。体外评估表明，与基准的SM-102 LNPs（67.4%）相比，R4H6C-DOPE（85.1%）和R5H5C-DOPE（89.5%）的基因沉默效率更高，同时保持了99%的细胞活力。R5H5C-DOPE表现出优异的广谱传递，mRNA和pDNA的转染效率分别为74.8%和92.1%。值得注意的是，R3H7C-DOPE的pDNA表达量比SM-102增加了11倍。体内研究显示，R3H7C-DOPE具有优越的肝脏靶向性，对PCSK9的抑制作用（28天时残留表达14.1±7.3%）是SM-102的2倍（7天时残留表达53.8±41.2%）。R5H5C-DOPE表现出显著的肝外靶向性，90%的肺定位，有效克服了传统LNPs的肝向性。综合安全性评估显示，RmHnC-DOPE制剂具有出色的生物相容性，在小鼠品系中具有100%的存活率，与sm -102引起的严重毒性和死亡率形成鲜明对比。长期研究证实了持续的耐受性，保留了器官功能和最小的炎症反应。这个多功能平台结合了卓越的生物相容性，精确的组织靶向性和合成可及性，为跨越肝沉默和肝外治疗的多种基因传递应用提供了临床可行的解决方案。

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来源期刊

Bioactive Materials Biochemistry, Genetics and Molecular Biology-Biotechnology

CiteScore

28.00

自引率

6.30%

发文量

436

审稿时长

20 days

期刊介绍： Bioactive Materials is a peer-reviewed research publication that focuses on advancements in bioactive materials. The journal accepts research papers, reviews, and rapid communications in the field of next-generation biomaterials that interact with cells, tissues, and organs in various living organisms. The primary goal of Bioactive Materials is to promote the science and engineering of biomaterials that exhibit adaptiveness to the biological environment. These materials are specifically designed to stimulate or direct appropriate cell and tissue responses or regulate interactions with microorganisms. The journal covers a wide range of bioactive materials, including those that are engineered or designed in terms of their physical form (e.g. particulate, fiber), topology (e.g. porosity, surface roughness), or dimensions (ranging from macro to nano-scales). Contributions are sought from the following categories of bioactive materials: Bioactive metals and alloys Bioactive inorganics: ceramics, glasses, and carbon-based materials Bioactive polymers and gels Bioactive materials derived from natural sources Bioactive composites These materials find applications in human and veterinary medicine, such as implants, tissue engineering scaffolds, cell/drug/gene carriers, as well as imaging and sensing devices.