BIOMACROMOLECULES
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2025
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IF 5.4
Yuduo Gao,Luwei Zhang,Ziyue Wang,Hao Bai,Chengfan Wu,Qi Shuai,Yunfeng Yan
mRNA-based therapies hold tremendous promise for treating various diseases, yet their clinical success is hindered by delivery challenges. This study developed a library of 140 lipocationic Poly(β-amino ester)s (PBAEs) and formulated lipid-polymer hybrid nanoparticles (LPHs) with four helper lipids, including 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), to enhance mRNA delivery. Initial in vitro screening of four representative PBAEs identified the D/P4-1 formulation (DOTAP/PBAE molar ratio of 4:1) as the most effective. Further screening of the library using this formulation identified eight top-performing LPHs. In vivo experiments confirmed high luciferase expression in the spleen and lungs of mice following intravenous administration of Luc mRNA-loaded LPHs. Detailed analysis revealed that DOTAP incorporation influenced LPH properties, including apparent pKa, surface charge, and internal hydrophobicity, enabling enhanced mRNA release and cellular uptake. This study demonstrates potent approaches to modulate PBAE-lipid nanoparticle properties by altering PBAE structures and nanoparticle composition, offering insights for designing effective hybrid carriers for mRNA therapeutics.
研究领域:
药学
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纳米技术
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分子生物学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2026
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IF 5.9
Keyi Chen,Meihong Ding,Shasha Lu,Yu Zhou,Yumeng Ye,Bo Yu,Ni Xie,Guilin Cheng
Lipid nanoparticles (Lips) are studied as drug delivery systems for superior biocompatibility, low toxicity, and high encapsulation efficiency. Their size, charge, and hydrophilicity are tunable via material composition and functional groups for tailored tissue distribution. In biological environments, Lip adsorbs proteins to form a "protein corona (PC)," which alters its physicochemical property and biological interaction. Nevertheless, the mechanisms of PC regulating Lip-tissue targeting remain unclear, with limitations of inaccurate in vivo fluorescence quantification and poor stability. To track Lip fate in vivo, self-synthesized aggregation-induced emission fluorescent nanoparticle (AIEgen R1) was used as a template and encapsulated by Lips with varied material compositions and proportions to prepare visualized nanoliposome R1@Lip. In contrast, using ergosterol (ERG) as membrane material, R1@Lip-4 exhibited fluorescence signals of 55.4% in liver and 13.3% in lung tissue, with stronger liver-targeting than cholesterol (CHOL)-based ones. In vitro uptake validated tissue tropism. Proteomic analysis demonstrated that 8% DOTAP led to an increase in liver-targeting proteins (e.g., TRFE, FIBA), while 30% DOTAP content resulted in the enrichment of lung-targeting proteins such as ANXA1 and PDLI1. Substituting CHOL with ERG led to a reduction in lung-targeting proteins while increasing liver-targeting proteins (e.g., FIBA). This indicated that R1@Lip-4 with 30% cationic exhibited a wider liver distribution than R1@Lip-3. These findings establish an "R1@Lip-PC-tissue targeting" relationship, facilitating precise modulation of PC properties through Lip formulation to enhance tissue targeting.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2026
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IF 7.8
Yuduo Gao,Yiqing Chen,Zhenghao Hu,Ziyue Wang,Dongchang Sun,Chengfan Wu,Qi Shuai,Yunfeng Yan
Heat shock protein 47 (HSP47) regulates collagen synthesis and fibrosis, which makes it a promising target for controlling pulmonary fibrosis. However, challenges such as cell-selective and efficient drug delivery continue to impede the verification and translation of HSP47-targeted therapies. The CRISPR/Cas9 system can effectively inhibit the overexpression of HSP47 within fibrotic lesions while significantly reducing off-target effects. This study develops a class of lipid nanoparticles (LNPs) capable of codelivering Cas9 mRNA and sgHSP47 to fibroblasts. By incorporation of an additional cationic effector molecule, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), these LNPs achieve differential delivery across various cell lines and markedly enhance uptake efficiency in fibroblasts. This system mediates effective HSP47 knockdown in L929 cells and the lungs of C57BL/6 mice, leading to reduced collagen deposition and fibroblast activation in bleomycin-induced idiopathic pulmonary fibrosis (IPF) mice. This LNP platform holds substantial potential for gene editing-based IPF therapy and provides valuable insights for the efficient and selective delivery of CRISPR/Cas9 systems.
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2025
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IF 19
Shuai Wu,Ya Wang,Yunfan Li,Minyao Qiu,Yuan Zhong,Maolan Zhang,Haifeng Yang,Jianshu Li,Wei Wu
Clinical treatment of temozolomide (TMZ)-resistant glioblastoma (GBM) remains a significant challenge. This study aims to develop a multifunctional biomimetic Nano-AUTAC (BM@pPPD/TMZ) that can selectively degrade β-catenin via autophagy, thereby overcoming TMZ resistance in GBM. BM@pPPD/TMZ is capable of penetrating the blood-brain barrier (BBB), targeting GBM lesions via microglia-derived membrane camouflage, and inducing degradation of β-catenin through the autophagy-lysosomal pathway. For improving the selective and efficient degradation of β-catenin, BM@pPPD/TMZ is functionalized with a tri-functional peptide comprising a β-catenin-binding domain, a cathepsin B (CTSB)-cleavable GLFG linker, and a phosphatidylserine (PS)-targeting motif. In the GBM microenvironment, the elevated CTSB triggers linker cleavage, promoting membrane shedding and enhancing the cellular uptake. Meanwhile, the incorporation of the cationic lipid DOTAP promotes autophagosome formation, further facilitating degradation of β-catenin. Both in vitro and in vivo studies demonstrate that BM@pPPD/TMZ is able to effectively penetrate the BBB and accumulate within tumor lesion, concurrently promoting β-catenin degradation and MGMT downregulation. This finding provides a promising nanotherapeutic strategy for overcoming TMZ resistance and improving GBM therapeutic efficacy.
研究领域:
纳米医学
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癌症治疗
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分子生物学
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神经肿瘤学
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自噬研究
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药物递送
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
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2021
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IF 9.229
Lan Wu,Lin-Ping Wu,Jingya Wu,Jin Sun,Zhonggui He,Cristina Rodríguez-Rodríguez,Katayoun Saatchi,Lea Ann Dailey,Urs O. Häfeli,Dongmei Cun,Mingshi Yang
Pulmonary delivery of small interfering RNA (siRNA)-based drugs is promising in treating severe lung disorders characterized by the upregulated expression of disease-causing genes. Previous studies have shown that the sustained siRNA release in vitro can be achieved from polymeric matrix nanoparticles based on poly(lactide-co-glycolide) (PLGA) loaded with lipoplexes (LPXs) composed of cationic lipid and anionic siRNA (lipid–polymer hybrid nanoparticles, LPNs). Yet, the in vivo efficacy, potential for prolonging the pharmacological effect, disposition, and safety of LPNs after pulmonary administration have not been investigated. In this study, siRNA against enhanced green fluorescent protein (EGFP-siRNA) was either assembled with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) to form LPX or co-entrapped with DOTAP in PLGA nanoparticles to form LPNs. The disposition and clearance of LPXs and LPNs in mouse lungs were studied after intratracheal administration by using single-photon emission computed tomography/computed tomography (SPECT/CT) and gamma counting. Fluorescence spectroscopy, Western blot, and confocal laser scanning microscopy were used to evaluate the silencing of the EGFP expression mediated by the LPXs and LPNs after intratracheal administration to transgenic mice expressing the EGFP gene. The in vivo biocompatibility of LPXs and LPNs was investigated by measuring the cytokine level, total cell counts in bronchoalveolar lavage fluid, and observing the lung tissue histology section. The results showed that the silencing of the EGFP expression mediated by LPNs after pulmonary administration was both prolonged and enhanced as compared to LPXs. This may be attributed to the sustained release characteristics of PLGA, and the prolonged retention in the lung tissue of the colloidally more stable LPNs in comparison to LPXs, as indicated by SPECT/CT. The presence of PLGA effectively alleviated the acute inflammatory effect of cationic lipids to the lungs. This study suggests that PLGA-based LPNs may present an effective formulation strategy to mediate sustained gene silencing effects in the lung via pulmonary administration.
研究领域:
药剂学
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纳米技术
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分子生物学
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肺科学
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产品关联
DOI
PubMed
高影响因子
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