JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Kangzeng Wu,Fengwei Xu,Yongchao Dai,Shanshan Jin,Anjie Zheng,Ning Zhang,Yuhong Xu
Lipid nanoparticles (LNPs) used for nonviral gene delivery have achieved significant success, particularly in COVID-19 mRNA vaccines. LNPs are routinely characterized by their particle size, polydispersity, and mRNA loading efficiency. However, the internal structure of these particles has not been specified, despite evidence showing that LNPs can be highly heterogeneous, with variations in lipid composition and preparation methods. How these structural features contributed to mRNA LNP vaccine activities is also unclear. In this study, we prepared LNPs with distinctly different internal structures. They were named the emulsion-like LNPs (eLNPs) and membrane-rich LNPs (mLNPs) respectively and compared with the classic “bleb” structure LNPs (cLNPs). The eLNPs contained higher molar percent of the ionizable lipid and lower molar percent of DSPC and cholesterol. The different lipid organization structures lead to varying mRNA delivery activities in vitro and in vivo. After intramuscular injection, eLNPs remained at the injection site and expressed antigens locally. The resulted immune responses had a very fast onset (higher titer at week 2) and lasted longer and stronger (higher titers at week 8) than other LNPs (cLNPs and mLNPs). We hypothesize that the rapid onset and local expression of antigens by muscle cells in the eLNP groups may be favored by the antigen recognition and presentation process, despite the overall mRNA expression activities was not as high especially in liver and other organ. Our data support that eLNPs are potentially the more suitable delivery system for mRNA vaccine due to their high immunogenicity and low systemic toxicity.
研究领域:
药学
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免疫学
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纳米技术
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疫苗学
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PubMed
高影响因子
Materials Today
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2026
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IF 22
Haowei Zu,Qiyue Sun,Tianyu Song,Xingdi Cheng,Shuai Liu,Chen Yang,Yixing Wen,Jingjiao Li,Rui Xie,Gongchen Wang,Jiaqi Lin,Jing Sun,Xueguang Lu
Mycoplasma pneumoniae (MP) remains a leading cause of community-acquired pneumonia in children and older adults, yet no licensed vaccine exists and intramuscular approaches fail to intercept infection at its mucosal portal. Here, we engineered an mRNA vaccine encoding four conserved MP antigens, formulated in tamibarotene-loaded lipid nanoparticles optimized for both intramuscular (IM) and intranasal (IN) administration. In mice, IM vaccination elicited high serum IgG and splenic T cell responses but generated negligible mucosal immunity. By contrast, IN administration induced robust bronchoalveolar IgA and expanded lung-resident memory T cells, while systemic IgG levels remained lower than with IM. Functionally, IN immunization conferred superior protection against MP challenge compared to IM immunization, reducing pulmonary MP load and lung pathology while demonstrating broad–spectrum efficacy against both MP strains 1 and 2. These head-to-head comparisons position intranasal mRNA‐LNP vaccination as a transformative strategy for safe, broadly protective vaccine for MP.
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高影响因子
Science Bulletin
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2026
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IF 20.7
Yi Song,Zhangchi Dongye,Jiaxi Yao,Xiaonan Zhao,Tao Mo,Shiyu Yang,Cong Sun,Tingting Zhao,Jian Li,Yuzhang Wu
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). Current non-specific immunosuppressive therapies carry risks of infection and malignancy. Antigen-specific tolerance induction presents a promising alternative. Here, we developed a messenger RNA-lipid nanoparticle (mRNA-LNP) vaccine (LiH-LNPs) encoding a tandem fusion of epitopes from three MS-associated myelin antigens. LiH-LNPs alleviated inflammatory infiltration and demyelination in experimental autoimmune encephalomyelitis (EAE). Single-cell RNA sequencing revealed that LiH-LNPs reshaped the spinal cord microenvironment toward inflammation resolution by reducing the abundance and inflammatory activity of infiltrating myeloid cells and activated microglia, inducing apoptosis of encephalitogenic T cells while increasing regulatory T (Treg) cell abundance and suppressive activity. These findings provide mechanistic insights into antigen-specific immunotherapy for MS and highlight the potential application of mRNA vaccine-based antigen-specific therapy for autoimmune diseases. Download: Download high-res image (292KB) Download: Download full-size image
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高影响因子
Journal of the American Chemical Society
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2026
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IF 16.6
Chenlong Wei,Xinzhu Shan,Yuxuan Huang,Bin Ma,Zhiqiang Zhao,Yian Fang,Chengrui Bai,Zihan Zhang,Peng Zhao,Huijuan Zhang,Yu Hou,Tianjiao Ji,Zhongtang Li,Song Song,Fei Xie,Lei Miao
The inefficient delivery of lipid nanoparticles (LNPs)-encapsulated mRNA to activated fibroblasts in fibrotic tissues remains a major challenge for antifibrotic therapy. To overcome this, we develop a fibrosis organ and cell unified-targeting system (FOCUS) for mRNA delivery with LNPs. FOCUS LNPs combines an ionizable lipid library (synthesized via Ugi multicomponent reactions) with fibroblast activation protein-α (FAP)-targeting lipid-like ligands. These LNPs achieve ∼3-fold and ∼12-fold greater mRNA expression in fibrotic liver and lung, along with ∼2–5-fold higher fibroblast distribution─unattainable by organ- or ligand-only targeting. As proof of concept, Pentraxin-2 mRNA (mPTX-2)-loaded FOCUS LNPs drive localized PTX-2 production in murine models of pulmonary and hepatic fibrosis, reducing collagen deposition by 60–80% while avoiding systemic side effects like impaired wound healing. Mechanistically, mPTX-2 FOCUS LNPs suppress monocyte-to-fibrocyte differentiation, M2 macrophage polarization, and fibroblast activation. This work establishes a precision mRNA delivery platform for fibrotic diseases, offering a safer and more effective therapeutic strategy.
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PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2025
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IF 14.6
Xiaoxuan Hong,Xianfu Li,Xiaolu Han,Jinghu Lou,Yue Li,Jintao Lin,Yi Cheng,Haonan Xing,Hui Zhang,Xiwei Wang,Shuang Zhang,Nan Liu,Zengming Wang,Chunying Cui,Aiping Zheng
During the COVID-19 pandemic, the use of lipid nanoparticles (LNPs) augmented the development of mRNA vaccines. However, their ultralow-temperature storage and transportation requirements, as well as their heavy reliance on injection by professional medical staff, have limited large-scale vaccination in many developing countries. Herein, we developed a simple and widely deployable microneedle (MN) vaccine delivery system (mLNP-man-MN) for mannose-modified LNPs (mLNP-man) loaded with mRNA encoding the SARS-CoV-2 spike receptor-binding domain by utilizing three-dimensional printing and polydimethylsiloxane micro molding methods. This delivery system is composed of a dissolvable polymer mixture that was optimized for high bioactivity by screening formulations in vitro . We have demonstrated that this MN system can maintain the physicochemical properties and bioactivity of the mRNA-LNP complex even when stored at 4 °C for at least one month or at 25 °C for two weeks. Moreover, mLNP-man-MNs target the epidermis and dermis, which are rich in antigen-presenting cells, thereby eliciting effective innate immune responses and inducing robust systemic humoral responses, as well as multifunctional cellular immunity in the spleen. Importantly, the MN system induced a certain level of pulmonary T-cell responses compared to those induced by intramuscular injections, thereby providing some protection against lung invasion by the SARS-CoV-2 pseudovirus in mice.
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PubMed
高影响因子
ELECTROPHORESIS
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2026
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IF 2.5
Shang-Yin Wu,Yun-Jie He,Zhi-Jun Guo,Min Wang,Chang-Yun Xiong,Tingjun Hou,Bin Di,Wei-Jie Fang
mRNA-based vaccines and self-amplifying mRNA (saRNA) have gained growing attention for disease prevention and treatment, but precise detection of low-concentration RNA (including mRNA–lipid nanoparticles, mRNA–LNPs) stability and integrity remains challenging—limiting quality control of RNA-based therapeutics. Capillary electrophoresis (CE)-based instruments show potential, yet suitable concentration strategies for low-abundance, labile RNAs are lacking. This study established two distinct concentration methods (freeze-drying and ultrafiltration) applicable to mRNA, mRNA–LNPs, and saRNA formulations, enabling the conversion of dilute solutions to high-concentration preparations while preserving the structural and molecular integrity of the target nucleic acids. Subsequent stability evaluations and conventional high-performance liquid chromatography analyses of the concentrated products verified their superior storage stability and strong practical applicability. This article aims to reduce the difficulty of RNA integrity assessment and improve the accuracy of detecting various low-concentration RNA samples that may arise in the future.
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高影响因子
iScience
·
2026
·Vol. 29
·期 10
·117519
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IF 4.5
Ziqi Wen,Yiling Long,Wenjing Shi,Wenjing Song,Rongjun Xu,Xingri Zhan,Xiuyuan Wang,Rui Su,Yu Wang,Jia Fei
PAH sa-mRNA-LNP enables sustained PAH expression in vitro and in vivo • PAH sa-mRNA-LNP achieves efficacy at one-sixth the dose of nr-mRNA-LNP • A single PAH sa-mRNA-LNP dose maintains physiological Phe levels in Pah-KO mice • Repeated PAH sa-mRNA-LNP dosing shows favorable tolerability in Pah-KO mice Summary Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficient phenylalanine hydroxylase (PAH) activity, with current pharmacotherapies showing limited response rates and age-dependent restrictions. We compared two liver-targeted lipid nanoparticle formulations delivering PAH-encoding mRNA—a self-amplifying construct (saRNA) and a conventional non-replicating counterpart (nr-mRNA)—in Pah-knockout mice. Both constructs reduced circulating phenylalanine (Phe) after a single intravenous injection. The saRNA formulation achieved comparable efficacy at one-sixth the nr-mRNA dose and maintained physiological Phe levels for 14 days, whereas nr-mRNA produced only transient reductions. Repeated saRNA administration was well tolerated, with no detectable immunogenicity or hepatic toxicity. These results establish that saRNA-mediated PAH replacement provides sustained activity with substantial dose reduction, overcoming the short-lived effect of non-replicating mRNA. This platform may inform broader strategies for durable enzyme therapy in inherited metabolic diseases requiring liver-restored function. Download: Download high-res image (147KB) Download: Download full-size image
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高影响因子
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