COLLOIDS AND SURFACES B-BIOINTERFACES
·
2025
·
IF 5.6
Longyu Wang,Yichen Li,Pingge Jiang,Hao Bai,Chengfan Wu,Qi Shuai,Yunfeng Yan
Lipid nanoparticles (LNPs) have shown promising performance in mRNA delivery. Nevertheless, a thorough understanding of the relationship between mRNA delivery efficacy and the structure of LNPs remains imperative. In this study, we systematically investigated the effects of additional hydrophobic amines on the physicochemical properties of mRNA LNPs and their delivery efficacy. The results indicated that this influence depended on the chemical structure of the additional amines and the structure of the lipid carriers. The appropriate addition of the hydrophobic amine 2C8 to lipid carriers with structural 2C8 or 2C6 tails significantly increased their mRNA delivery efficiency. In contrast, the addition of hydrophobic amine C18 to LNPs resulted in a decrease in mRNA delivery efficiency, while the addition of hydrophobic amines 2C6 and C8, as well as alkanes C12' and C16', had relatively little effect on mRNA delivery. Further investigations demonstrated that the appropriate addition of 2C8 could reduce LNP size, moderate internal hydrophobicity and LNP stability, facilitate mRNA release, enhance cellular uptake, and improve intracellular transportation of LNPs, thereby achieving superior mRNA delivery efficiency. These findings highlight the important role of additional hydrophobic amines in mRNA delivery with LNPs and provide valuable insights for the advancement of mRNA delivery carriers.
研究领域:
分子生物学
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Kexin Cui,Zhang Fangming,Tianzi Shi,Siyu Zhao,Yixuan Zhou,Xiong Liu,Yong Hu,Zhaoyu Hu,Li Kong,Zhiping Zhang
Ionizable lipids are crucial for the effective delivery of mRNA by using lipid nanoparticles (LNPs). Endowing ionizable lipids with tailored biological properties could potentially augment the therapeutic efficacy of mRNA-based treatments. Herein, a functional vitamin E (VE)-based lipid library with distinct head groups was designed and synthesized. Due to the presence of VE, these lipids inherently exhibited immunomodulatory properties, including the promotion of cellular uptake, dendritic cells maturation, and antigen presentation. Through iterative optimization of the LNP components and the architecture of ionizable lipids, the correlation between the structure of ionizable lipids and their mRNA delivery efficiency has been established, leading to the finding of the most effective delivery formulation. Benefiting from the high mRNA delivery efficiency and the immunomodulatory function of LNPs themselves, VE-based LNPs have demonstrated complete remission in colon cancer by delivering mIL-12, which offered a beneficial combination with immune checkpoint blockade. The proposed functional LNPs were anticipated to furnish potential delivery systems for mRNA-based cancer treatments.
研究领域:
生物技术
·
肿瘤学
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Menghua Gao,Jiafeng Zhong,Xinxin Liu,Yanjun Zhao,Dingcheng Zhu,Xiaohuo Shi,Xuehan Xu,Qin Zhou,Wenjing Xuan,Yue Zhang,Yaofeng Zhou,Jianjun Cheng
Organ- and cell-specific delivery of mRNA via modular lipid nanoparticles (LNPs) is promising in treating various diseases, but targeted cargo delivery is still very challenging. Most previous work focuses on screening ionizable and helper lipids to address the above issues. Here, we report the multifacial role of PEGylated lipids in manipulating LNP-mediated delivery of mRNA to the liver. We employed the typical excipients in LNP products, including DLin-MC3-DMA, DPSC, and cholesterol. Five types of PEGylated lipids were selected, and their molar ratio was fixed at 1.5% with a constant PEG molecular weight of 2000 Da. The architecture of steric lipids dramatically affected the in vitro gene transfection, in vivo blood clearance, liver deposition, and targeting of specific cells, all of which were closely linked to the de-PEGylation rate. The fast de-PEGylation resulted in short blood circulation and high accumulation in the liver. However, the ultrafast de-PEGylation enabled the deposition of more LNPs in Kupffer cells other than hepatocytes. Surprisingly, simply changing the terminal groups of PEGylated lipids from methoxyl to carboxyl or amine could dramatically increase the liver delivery of LNPs, which might be associated with the accelerated de-PEGylation rate and enhanced LNP–cell interaction. The current work highlights the importance of manipulating steric lipids in promoting mRNA delivery, offering an alternative approach for formulating and optimizing mRNA LNPs.
研究领域:
分子生物学
·
药物递送
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Yichen Li,Yi Cao,Hao Bai,Luwei Zhang,Baiqiu Chen,Chengfan Wu,Qi Shuai,Yunfeng Yan
The application of mRNA-based therapies has gained significant attention in recent years, with lipid nanoparticles (LNPs) emerging as key delivery vehicles. However, challenges remain in optimizing delivery efficiency and targeting tissues beyond the liver, particularly for immunotherapy. In this study, we constructed novel lipids with disulfide bonds in the linkers and utilized the redox responsiveness of these bonds in the reductive microenvironment of tumor or immune cells to enable robust splenic mRNA delivery and potent cancer immunotherapy. A library of 119 lipids was synthesized by conjugating hydrophilic amines, disulfide-containing linkers, and hydrophobic amines via sequential aza-Michael addition. In vitro screening identified lipids with longer, branched hydrophobic tails, particularly 2C10, as leading carriers for mRNA delivery. Compared to conventional LNPs without disulfide linkers, disulfide-containing LNPs showed smaller size, higher mRNA binding, and enhanced mRNA release in the presence of GSH, with predominantly spleen-targeted in vivo delivery. Encapsulation with OVA mRNA promoted CD4 + and CD8 + T cell differentiation, leading to significant tumor regression in a melanoma mouse model. These findings highlight the potential of redox-responsive LNPs for targeted mRNA delivery and cancer immunotherapies.
研究领域:
生物技术
·
药理学
·
免疫学
✓ 已验证
产品关联
DOI
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-15
·
IF 15.7
Liu Zhen,Wu Jiacai,Wang Ning,Lin Yongqi,Song Ruiteng,Zhang Min,Li Bin
Despite remarkable progress in designing RNA delivery systems, endosomal escape remains a recognized challenge for efficient RNA delivery. In this study, we develop a robust mRNA delivery platform termed endosomolytic chloroquine-like optimized lipid nanoparticles (ecoLNPs) for versatile mRNA delivery in vitro and in vivo via integrating the signature scaffold extracted from endosomolytic chloroquine into ionizable lipids. RNase-resistant ecoLNPs are capable of delivering a broad variety of mRNA payloads to diverse cell types, even hard-to-transfect 3D cells, with an efficiency of up to 18.9-fold higher than that of commercial transfection reagents. The pH-responsive endosomolytic activity of ecoLNPs can be largely attributed to the proton sponge effect and saposin B-promoted membrane disruption. In vivo, ecoLNPs enable potent local and systemic mRNA delivery and exhibit comparable potency to the clinically approved mRNA vaccine carrier, but strong tropism for lymph nodes following intramuscular injection. Furthermore, ecoLNPs are able to retain in vivo delivery potency for at least one week under non-frozen conditions and induce efficient genome editing in transgenic mice. Overall, the structure-guided integration strategy provides a pathway for de novo design of endosomolytic mRNA delivery systems.
研究领域:
分子生物学
·
纳米医学
·
药物递送
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Kexin Zhang,Zhen Xu,Zexiu Xiao,Fei Cao,Jing Wang,Yuandong Xu,Winson M.J. Ma,Sihui Long,Gao-Feng Zha
Lipid nanoparticles (LNPs) have emerged as a clinically validated platform for cancer immunotherapy; however, challenges remain in optimizing RNA delivery and promoting synergistic immune activation. To address these issues, we developed a modified LNP system that incorporates α-galactosylceramide (α-GalCer), a CD1d-binding glycolipid known to activate invariant natural killer T (iNKT) cells. Through structural optimization, we created the α-GalCer-LNP (G-LNP), which offers three primary advantages over conventional four-component LNPs: (1) enhanced mRNA transfection efficiency due to improved endosomal/lysosomal escape, (2) increased capacity for in vivo DC transfection, leading to robust activation of tumor-specific CD8 + T cells via MHC-I and iNKT cells via the CD1d pathway, and (3) reprogramming of the tumor microenvironment, resulting in a 1.5-fold increase in iNKT cell infiltration and sustained elevation of IFN-γ (>24 h) in lymph nodes. In a TC-1 cervical carcinoma model, G-LNP induced complete tumor regression in 100 % of treated mice (compared to 42.85 % for standard LNP) and provided long-term protection against tumor rechallenge (lasting >100 days). Mechanistic studies showed that G-LNP preferentially targets CD11c + DC in the lymph nodes, facilitating coordinated antigen presentation and innate immune activation. This five-component engineering strategy establishes a versatile platform to enhance the functionality of LNPs for the development of next-generation cancer vaccines.
研究领域:
免疫学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Siyu Dong,Zhaoqi Pan,Mengchun Chang,Juanjuan Zhou,Mengke Zhang,Yashuang Chen,Ting Li,Ziwen Chen,Yuwan Gao,Sitao Xie,Wencan Wu,Xiangsheng Liu
Ionizable lipid serves as the key functional component in lipid nanoparticles (LNPs) for efficient mRNA delivery. This study aims to systematically evaluate clinically approved ionizable lipid DLin-MC3-DMA and SM102-based LNPs for ocular mRNA delivery, with a comprehensive assessment of their physicochemical characteristics, delivery efficiency, and biodistribution patterns within the ocular microenvironment. Enhanced green fluorescence protein or Luc encoding mRNA-loaded LNPs were formulated using microfluidic mixing technology and characterized by dynamic light scattering, ζ-potential measurements, and cryogenic transmission electron microscopy imaging. The two LNP systems with different ionizable cationic lipids demonstrated distinct capabilities for in vitro mRNA transfection and intraocular mRNA delivery following intravitreal administration. Notably, the SM102-LNPs exhibited superior performance compared to the MC3-LNPs, characterized by significantly higher transfection efficiency in retinal cells in vitro, and more efficient ocular expression with minimal systemic distribution in vivo. Safety assessment demonstrated that intravitreal administration of SM102-LNPs maintained excellent long-term biocompatibility throughout a five-month study period. The superior performance of SM102-LNPs establishes a promising platform for ocular mRNA therapeutics.
研究领域:
药理学
·
分子生物学
·
眼科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCONJUGATE CHEMISTRY
·
2025
·
IF 3.9
Sheng Lin,Xia Cheng,Xiyi Chen,Jinxuan He,Wenxiu An,Qiufang Bai,Qixian Chen,Lie Ma,Jianhua Hu,Yue Wang,Xiabin Lan
The refinement of dynamic molecular mechanisms regulating mRNA release kinetics represents a critical frontier in advancing the synthetic mRNA delivery systems. This study details the synthesis of an intriguing ROS-responsive cationic block copolymer (pM-pBD) via reversible addition−fragmentation chain transfer (RAFT) polymerization, employing biocompatible 2-methacryloyloxyethyl phosphorylcholine (MPC) and charge-reversible (2-acryloyl)ethyl(boronic acid benzyl)diethylammonium bromide (BD) as monomeric precursors. The synthesized copolymer facilitates electrostatic-driven self-assembly with anionic mRNA. Mechanistically, the pBD block exhibits ROS-mediated charge transition, enabling stimulus-dependent molecular decomposition and promoting mRNA payload liberation, thereby establishing spatial regulation of translational activity. Furthermore, intracellular ROS modulation experiments revealed that systemic ascorbic acid administration selectively enriches reactive oxygen species within tumor microenvironments. This redox microenvironment significantly amplifies pM-pBD nanocomplex-mediated mRNA expression by an order of magnitude across multiple carcinogenic cell lines, validating the ROS-responsive characteristics of our rationally designed delivery platform. In vivo studies demonstrated the highest mRNA expression levels in tumors when aided by ascorbic acid adjuvants, despite lower tumor accumulation of mRNA compared to renal and hepatic sequestration post intravenous administration of the pM-pBD nanocomplex. This spatial expression pattern correlates with ascorbic acid-mediated intratumoral ROS accumulation, which promotes cargo release and subsequent protein synthesis of approximately 6.4-fold enhancement. Our approach, integrating redox-responsive polymer design with organ-specific pharmacological modulation, signifies a transformative advancement in targeted nucleic acid delivery. By merging stimulus-responsive materials science with tumor microenvironment biology, this methodology provides a foundation for spatially controlled mRNA expression, presenting an innovative strategy for precision oncology applications.
研究领域:
生物材料
·
肿瘤学
·
药剂学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2025
·
IF 5.7
Lan Zhang,Ping Chen,Xiao-Li Tian,Yue Hu,Rong Wang,Ji Zhang
As mRNA vaccines continue to gain widespread attention, lipid nanoparticles (LNPs), the preferred platform for mRNA delivery, have become a key focus of development. 1, 4, 7, 10-Tetraazacyclododecane (cyclen), with its excellent protonation capability and ease of modification, has emerged as a promising candidate for the ionizable head group of lipid materials. In this study, a series of cyclen-based lipidoids with different linkages and hydrophobic tails were designed and conveniently synthesized. Structure-activity relationship studies were performed to screen out the carriers capable of efficient mRNA delivery and with potential for tumor therapeutic applications. In vivo biodistribution experiments in mice revealed that the lipidoid OEs-K, containing both hydroxyl and ester groups in its linkage, exhibited not only high mRNA delivery efficiency but also lymph node-targeting properties. Using a subcutaneous EG.7-OVA tumor model in mice, the delivery of tumor antigen OVA mRNA by the lipidoid material was evaluated for its antitumor immunotherapeutic potential. The results demonstrated that LNPs formulated with OEs-K promoted dendritic cell uptake in lymph nodes, effectively activated immune responses, and inhibited tumor growth. Hematological and histopathological evaluations indicated no significant toxicity to the body. This study might provide insights into the design and development of carrier materials for mRNA vaccines.
研究领域:
生物医学工程
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2025
·Vol. 17
·期 8
·950
·
IF 5.5
Wei Liu,Meihui Zhang,Huiyuan Lv,Chuanxu Yang
Background : Lipid nanoparticles (LNPs) represent one of the most effective non-viral vectors for nucleic acid delivery and have demonstrated clinical success in siRNA therapies and mRNA vaccines. While considerable research has focused on optimizing ionizable lipids and helper lipids, the impact of PEGylated lipid content on LNP-mediated mRNA delivery, especially in terms of in vitro transfection efficiency and in vivo performance, remains insufficiently understood. Methods : In this study, LNPs were formulated using a self-synthesized ionizable lipid and varying molar ratios of DMG-PEG2000. Nanoparticles were prepared via nanoprecipitation, and their physicochemical properties, mRNA encapsulation efficiency, cellular uptake, and transfection efficiency were evaluated in HeLa and DC2.4 cells. In vivo delivery efficiency and organ distribution were assessed in mice following intravenous administration. Results : The PEGylated lipid content exerted a significant influence on both the in vitro and in vivo performance of LNPs. A bell-shaped relationship between PEG content and transfection efficiency was observed: 1.5% DMG-PEG2000 yielded optimal mRNA transfection in vitro, while 5% DMG-PEG2000 resulted in the highest transgene expression in vivo. This discrepancy in optimal PEG content may be attributed to the trade-off between cellular uptake and systemic circulation: lower PEG levels enhance cellular internalization, whereas higher PEG levels improve stability and in vivo bioavailability at the expense of cellular entry. Furthermore, varying the PEG-lipid content enabled the partial modulation of organ distribution, offering a formulation-based strategy to influence biodistribution without altering the ionizable lipid structure. Conclusions : This study highlights the critical role of PEGylated lipid content in balancing nanoparticle stability, cellular uptake, and in vivo delivery performance. Our findings provide valuable mechanistic insights and suggest a straightforward formulation-based strategy to optimize LNP/mRNA systems for therapeutic applications.
研究领域:
药学
·
纳米技术
·
基因递送
·
生物医学工程
·
RNA治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Ping Chen,Xi He,Yue Hu,Xiao-Li Tian,Xiao-Qi Yu,Ji Zhang
In recent years, the application of mRNA vaccine-based tumor immunotherapy invigorated anti-tumor therapy. However, the low efficiency of mRNA delivery and the lack of targeting ability in vivo are the major obstacles to achieving highly efficient immunotherapy. In this work, we report a chemical library of amphiphilic carbon dots (ACDs) and the synthesized ACDs were applied to mRNA delivery, bio-imaging, and tumor immunotherapy. The ACDs can smoothly bind with mRNA to form ACDs@mRNA nanocomplexes, and the fluorescent properties of the ACDs afforded the nanoparticles with bio-imaging ability. By screening of the ACDs, O12-Tta-CDs were found to have optimal mRNA transfection efficiency and the ability of spleen-targeted delivery. In addition, O12-Tta-CDs can well transfect the immune cells and promote the maturation and antigen presentation of bone marrow-derived dendritic cells (BMDCs). Furthermore, O12-Tta-CDs@OVA-mRNA was successfully applied to inhibit tumor growth, and more specific T-cell infiltration was observed in spleen and tumors of mice after treatment in the E.G7-OVA tumor model. Besides, O12-Tta-CDs@OVA-mRNA also achieved a good therapeutic effect in tumor recurrence inhibition and tumor prophylactic experiments. This study provided a new direction for the design of mRNA vectors, which is promising in tumor immunotherapy.
研究领域:
生物医学工程
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioengineering & Translational Medicine
·
2025
·
IF 5.7
Lulu Chen,Bicheng Chen,Xiang Su
An abdominal aortic aneurysm (AAA) is a life-threatening vascular condition characterized by the dilation of the abdominal aorta, with ferroptosis playing a significant role in its pathogenesis. This study investigates the therapeutic potential of engineering biomimetic nanovesicles to deliver phosphatidylethanolamine-binding protein 1 (PEBP1) mRNA for inhibiting ferroptosis in vascular smooth muscle cells (VSMCs) and preventing AAA progression. Differential gene expression analysis of the AAA transcriptomic dataset GSE57691 identified 243 differentially expressed genes (DEGs), intersecting with 12 ferroptosis-related genes. Single-cell analysis of dataset GSE237230 highlighted PEBP1 as a key gene in VSMCs. Overexpression of PEBP1 in VSMCs enhanced proliferation, reduced reactive oxygen species (ROS) and iron levels, and inhibited apoptosis and ferroptosis via the NRF2/GPX4 axis. The engineered biomimetic nanovesicles demonstrated significant uptake by VSMCs and effective delivery of PEBP1 mRNA. In vivo studies confirmed that these nanovesicles substantially inhibited AAA progression in mice. This study presents a novel bioengineering approach for AAA treatment by targeting ferroptosis through PEBP1 mRNA delivery, offering a promising molecular strategy for the prevention and management of AAA.
研究领域:
生物医学工程
·
纳米技术
·
分子生物学
·
心血管疾病研究
·
基因治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）